Substituted pteridinones for the treatment of cancer

ABSTRACT

Compounds of Formula I, as shown below and defined herein: 
                         
pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including treatment of cancers, such as tumors driven or mediated at least in part by RSK. This Abstract is not limiting of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage of PCT/US2012/064596, filed Nov.12, 2012, which claims the benefit of U.S. Provisional Application No.61/558,223, filed Nov. 10, 2011.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT

Not Applicable

INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC

Not Applicable

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention pertains at least in part to cancer, chemicalcompounds, their preparation, formulation, and use in treatingconditions such as cancer.

2. Description of the Related Art

RSK has emerged as an anti-cancer target. Ribosomal S6 protein kinases(RSKs) are a family of highly conserved protein serine/threonine kinasesthat includes subfamilies p90 RSK and p70 RSK and belong to the AGCsuper family. T. L. Nguyen, Anti-Cancer Agents in Medicinal Chemistry,8, 710-716 (2008); Y. Romeo et al., Expert Opin. Ther. Targets,15(1):5-9 (2011).

There are four isoforms of p90 RSK (RSK 1-4) in vertebrates, whichexhibit variable tissue expression, and are activated in response togrowth factors, polypeptide hormones, neurotransmitters, and chemokines.RSK lies downstream of the MAPK signaling pathway and is directlyphosphorylated by ERK1/2. RSK activation was also found to be triggeredby p38 and ERK5, and FGFR3. RSK regulates cellular processes such ascell growth, motility, survival, and proliferation. Nguyen, Romeo,above.

RSK contributes to antiapoptosis signaling by phosphorylating BAD,C/EBPβ, and DAP kinase. RSK is a mediator of FGFR3, being phosphorylatedby it, and RSK is a regulator in cell transformations induced by tumorpromoters. Some RSK substrates are themselves cancer targets ofinterest, such as Myt1 and GSK-3. Nguyen, Romeo, above.

Deregulated RSK expression or activity has been associated with severaldiseases, including cancers such as breast, multiple myeloma, acutemyeloid leukemia, hand and neck cancer, osteosarcoma, and prostate. RSKhas been linked to HIV and Coffin-Lowry syndrome (CLS), caused by amutation in RSK2. A cardiovascular target of RSK is NHE1 and thus RSKinhibitors may be useful in treating cardiovascular disease.

RSK may be a promising target for treating cancers characterized byoncogenic Ras/MAPK signaling; and RSK2 has been the isoform most closelylinked with human cancers. Nguyen, Romeo, above.

Compounds disclosed as inhibitors of RSK have come from variouschemotypes. J. A. Smith et al., Cancer Res., 65(3), 1027-1034 (2005);Nguyen, above. The dihydropteridinone BI-D1870 was found to be a potentinhibitor of RSK1-4. G. P. Sapkota et al., Biochem J., 401, 29-38(2007).

The reader may also take note of: U.S. Pat. No. 5,424,311; U.S. Pat. No.6,806,272; U.S. Pat. No. 7,169,778; U.S. Pat. No. 7,759,347;US2002/0086866; US2006/0047118; US2007/0155730; US2008/0194572;US2009/0124628; US2010/0216726; US2011/0124634; WO2001/019825;WO2005/018531; WO2005/123736; WO2006/021547; WO2007/014838;WO2007/135374; WO2008/009909; WO2008/040951; WO2008/092831;WO2008/093075; WO2009/139834; WO2010/080712; WO2011/016472;WO2011/036566; EP0590428.

There is a need for effective therapies for use in proliferativedisease, including treatments for primary cancers, prevention ofmetastatic disease, and targeted therapies, including tyrosine kinaseinhibitors, such as RSK, including its individual isoforms. Thus,problems addressed by the present invention include the identificationof potent and selective RSK inhibitors that further preferably possessother generally desirable drug-like physico-chemical and biologicalproperties.

BRIEF SUMMARY OF THE INVENTION

The present invention includes all of the subject matter disclosedherein, including the compounds, their preparation and intermediates,formulations and products thereof, and their use in the treatment ofdisease, including in the treatment of cancers and other conditions,alone or in combination with other rationally selected active agents.

Among other things, the present invention addresses a desire for newanti-cancer agents, for small molecule agents that inhibit RSK, thatselectively inhibit RSK, and that further possess a profile lending toeffective pharmaceutical use, including physicochemical, PK, and PDproperties suitable for an oral pharmaceutical product.

In some aspects, the present invention concerns compounds of Formula I,as shown below and defined herein:

or a pharmaceutically acceptable salt thereof, wherein:

A₁ is N or C(R⁴); A₂ is C(O) or C(R⁵)(R⁶);

R¹ is phenyl optionally fused to ₅₋₁₀cyclic, or R¹ is ₅₋₆heteroaryloptionally fused to ₅₋₁₀cyclic, either of which is optionallysubstituted;

R² is optionally substituted phenyl or optionally substituted₅₋₆heteroaryl; or R² is H or optionally substituted C₁₋₈aliphatic thatis optionally interrupted by one or more heteroatoms;

R³ is C₄₋₈carbocyclic optionally fused to ₅₋₁₀cyclic or is ₅₋₆heteroaryloptionally fused to ₅₋₁₀cyclic, either of which is optionallysubstituted;

R⁴ is H, halo, C₁₋₃aliphatic, or —OC₁₋₃aliphatic; and

each R⁵ and R⁶ is independently H, C₁₋₆liphatic, or ₃₋₁₀cyclic, any ofwhich is optionally substituted, and wherein R⁵ and R⁶, together withthe atom to which they are attached, can form a ₃₋₆cyclic optionallyincluding one or more heteroatoms; and R² and R⁵, together with theatoms to which they are attached, can form a ₃₋₆cyclic optionallyincluding one or more heteroatoms.

In some aspects, compounds of the invention are inhibitors of kinases,including RSK1 and RSK2. In some aspects, compounds of the invention areselective inhibitors of one or more of RSK 1-4, or of all of RSK 1-4.

In some aspects, the invention includes treating disease, human disease,including cancers, mediated at least in part by RSK, characterized byderegulated RSK expression, oncogenic Ras/MAPK signaling, alone or incombination regimens with other active agents that are at any time knownto effective in such combination.

The invention includes the compounds and salts thereof, and theirphysical forms, preparation of the compounds, useful intermediates, andpharmaceutical compositions and formulations thereof.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

Not Applicable

DETAILED DESCRIPTION OF THE INVENTION

Compounds

In some aspects, the present invention concerns compounds and any saltsthereof of Formula I, as shown below and defined herein:

wherein:

A₁ is N or C(R⁴); A₂ is C(O) or C(R⁵)(R⁶);

R¹ is phenyl optionally fused to ₅₋₁₀cyclic, or R¹ is ₅₋₆heteroaryloptionally fused to ₅₋₁₀cyclic, either of which is optionallysubstituted; R² is optionally substituted phenyl or optionallysubstituted ₅₋₆heteroaryl; or R² is H or optionally substitutedC₁₋₈aliphatic that is optionally interrupted by one or more heteroatoms;

R³ is C₄₋₈carbocyclic optionally fused to ₅₋₁₀cyclic or is ₅₋₆heteroaryloptionally fused to ₅₋₁₀cyclic, either of which is optionallysubstituted;

R⁴ is H, halo, C₁₋₃aliphatic, or —OC₁₋₃aliphatic; and

each R⁵ and R⁶ is independently H, C₁₋₆aliphatic, or ₃₋₁₀cyclic, any ofwhich is optionally substituted, and wherein R⁵ and R⁶, together withthe atom to which they are attached, can form a ₃₋₆cyclic optionallyincluding one or more heteroatoms; and R² and R⁵, together with theatoms to which they are attached, can form a ₃₋₆cyclic optionallyincluding one or more heteroatoms.

The invention includes a subgenus 1 of Formula I, and its salts,wherein:

each R⁵ and R⁶ is independently H or C₁₋₆aliphatic optionallysubstituted by one or more halo, —OH, —OC₁₋₃aliphatic, —NR⁴⁰R⁴¹,₅₋₆heteroaryl, or —C(O)NR⁴⁰R⁴¹; and wherein R⁵ and R⁶, together with theatom to which they are attached, can form a ₃₋₆cyclic optionallyincluding one or more heteroatoms; and

each R⁴⁰ and R⁴¹ is independently H or C₁₋₃aliphatic, and R⁴⁰ and R⁴¹,together with the atom to which they are attached, can form a ₃₋₆cyclicoptionally including one or more heteroatoms.

The invention includes a subgenus 2 of Formula I or of subgenus 1, andits salts, wherein:

R¹ is phenyl optionally fused to ₅₋₁₀cyclic, or R¹ is ₅₋₆heteroaryloptionally fused to ₅₋₁₀cyclic, either of which is optionallysubstituted by one or more R⁷;

each R⁷ is independently halo, nitro, —CN, —OR¹⁰, —NR¹⁰R¹¹, —C(O)R¹⁰,—C(O)OR¹⁰, —C(O)NR¹⁰R¹¹, —SR¹⁰, —R¹⁰, —NR¹²C(O)NR¹⁰R¹¹, —OC(O)R¹⁰,—NR¹²C(O)R¹, —NR¹²C(O)OR¹⁰, —OC(O)NR¹⁰R¹¹, —C(O)—C(O)OR¹⁰, —S(O₁₋₂)R¹⁰,—S(O₁₋₂)NR¹⁰R¹¹, —NR¹²S(O₁₋₂)R¹⁰, —NR¹²S(O₁₋₂)NR¹⁰R¹¹, —NR¹²S(O₁₋₂)OR¹⁰,or —OS(O₁₋₂)NR¹⁰R¹¹; or —PR¹⁰R¹¹, —P(OR¹⁰)(OR¹¹), —PR¹⁰(OR¹¹),—P(O)R¹⁰R¹¹, —P(O)(OR¹⁰)(OR¹¹), —P(O)R¹⁰(OR¹¹), —BR¹⁰R¹¹,—B(OR¹⁰)(OR¹¹), —NHS(O)(R¹⁰)═NR¹¹, or —R¹⁰—S(O)(R¹¹)═NR¹²; wherein inthe case of a non-aromatic moiety, an R⁷ can also include oxo;

each R¹⁰, R¹¹, and R¹² is independently H or C₁₋₆aliphatic, eachindependently optionally substituted by one or more halo, oxo, nitro,—CN, —OR¹³, —NR¹³R¹⁴, —C(O)R¹³, —C(O)OR¹³, —C(O)NR¹³R¹⁴, —SR¹³, —R¹⁴,—NR¹⁵C(O)NR¹³R¹⁴, —OC(O)R¹³, —NR¹⁴C(O)R¹³, —NR¹⁴C(O)OR¹³, —OC(O)NR¹³R¹⁴,—C(O)—C(O)OR¹³, —S(O₁₋₂)R¹³, —S(O₁₋₂)NR¹³R¹⁴, or —NR¹³S(O₁₋₂)R¹⁴;—NR¹⁵S(O₁₋₂)NR¹³R¹⁴, —NR¹⁵S(O₁₋₂)OR¹³, or —OS(O₁₋₂)NR¹³R¹⁴, or by—PR¹³R¹⁴, —P(OR¹³)(OR¹⁴), PR¹³(OR¹⁴), —P(O)R¹³R¹⁴, —P(O)(OR¹³)(OR¹⁴),—P(O)R¹³(OR¹⁴), —BR¹³R¹⁴, —B(OR¹³)(OR¹⁴), NHS(O)(R¹³)═NR¹⁴, or—R¹³—S(O)(R¹⁴)═NR¹⁵;

wherein any R¹⁰/R¹¹ pair attached to the same atom, together with saidatom to which they are attached, can form a ₃₋₆cyclic that can includeone or more heteroatoms selected from O, NR¹⁸, or S(O₀₋₂);

each R¹³, R¹⁴, and R¹⁵ is independently H or C₁₋₃aliphatic, eachindependently optionally substituted by one or more halo, —CN, —OR¹⁶,—NR¹⁶R¹⁷, —C(O)R¹⁶, —C(O)OR¹⁶, —C(O)NR¹⁶, or —OC(O)R¹⁶;

wherein any R¹³/R¹⁴ pair attached to the same atom, together with saidatom to which they are attached, can form a ₃₋₆cyclic that can includeone or more heteroatoms selected from O, NR¹⁹, or S(O₀₋₂); and

each R¹⁶, R¹⁷, R¹⁸, and R¹⁹ is independently H or C₁₋₃aliphatic.

The invention includes a subgenus 3 of Formula I or of subgenera 1 or 2,and its salts, wherein:

R² is phenyl or ₅₋₆heteroaryl, each optionally substituted by one ormore R²⁰;

or R² is C₁₋₈aliphatic optionally interrupted by one or more heteroatomsand optionally substituted by one or more R²¹;

each R²⁰ and R²¹ is independently oxo, —R²², halo, —CN, —OR²², —SR²²,—NR²²R²³, —C(O)R²², —C(O)OR²², —C(O)NR²², —OC(O)R²², NR²²C(O)R²³,—S(O₁₋₂)R²², —S(O₁₋₂)NR²²R²³, or —NR²²S(O₁₋₂)R²³;

each R²² and R²³ is independently H or C₁₋₃aliphatic, each independentlyoptionally substituted by one or more oxo, —R⁵⁰, halo, —CN, —OR⁵⁰,—SR⁵⁰, —NR⁵⁰R⁵¹, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)NR⁵⁰, —OC(O)R⁵⁰, NR⁵⁰C(O)R⁵¹,—S(O₁₋₂)R⁵⁰, —S(O₁₋₂)NR⁵⁰R⁵¹, or —NR⁵⁰S(O₁₋₂)R⁵¹;

wherein any R²²/R²³ pair attached to the same atom, together with saidatom to which they are attached, can form a ₃₋₆cyclic that can includeone or more heteroatoms selected from O, NR⁵², or S(O₀₋₂); and

each R⁵⁰, R⁵¹ and R⁵² is independently H or C₁₋₃aliphatic.

The invention includes a subgenus 4 of Formula I or of subgenera 1-3,and its salts, wherein:

R³ is phenyl optionally fused to ₅₋₁₀cyclic, or R³ is ₅₋₆heteroaryloptionally fused to ₅₋₁₀cyclic, either of which is optionallysubstituted by one or more R⁸;

each R⁸ is independently halo, nitro, —CN, —OR³⁰, —NR³⁰R³¹, —C(O)R³⁰,—C(O)OR³⁰, —C(O)NR³⁰R³¹, —SR³⁰, —R³⁰, —NR³²C(O)NR³⁰R³¹, —OC(O)R³⁰,—NR³²C(O)R³⁰, —NR³²C(O)OR³⁰, —OC(O)NR³⁰R³¹, —C(O)—C(O)OR³⁰, —S(O₁₋₂)R³⁰,—S(O₁₋₂)NR³⁰R³¹, —NR³²S(O₁₋₂)R³⁰, —NR³²S(O₁₋₂)NR³⁰R³¹, —NR³¹S(O₁₋₂)OR³²,or —OS(O₁₋₂)NR³⁰R³¹; or —PR³⁰R³¹, —P(OR³⁰)(OR³¹), —PR³⁰(OR³¹),—P(O)R³⁰R³¹, —P(O)(OR³⁰)(OR³¹), —P(O)R³⁰(OR³¹), —BR³⁰R³¹,—B(OR³⁰)(OR³¹), —NHS(O)(R³⁰)═NR³¹, or —R³⁰—S(O)(R³¹)═NR³²; wherein inthe case of a non-aromatic moiety, an R⁷ can also include oxo;

each R³⁰, R³¹, and R³² is independently H or C₁₋₆aliphatic, eachindependently optionally substituted by one or more halo, oxo, nitro,—CN, —OR³³, —NR³³R³⁴, —C(O)R³³, —C(O)OR³³, —C(O)NR³³R³⁴, —SR³³, —R³⁴,—OC(O)R³³, —NR³⁴C(O)R³³, —NR³⁴C(O)OR³³, —N═CR³³R³⁴, —OC(O)NR³³R³⁴,—C(O)—C(O)OR³³, —S(O₁₋₂)R³³, —S(O₁₋₂)NR³³R³⁴, or —NR³³S(O₁₋₂)R³⁴; or by—PR³³R³⁴, —P(OR³³)(OR³⁴), —PR³³(OR³⁴), —P(O)R³³R³⁴, —P(O)(OR³³)(OR³⁴),—P(O)R³³(OR³⁴), —BR³³R³⁴, —B(OR³³)(OR³⁴), —NHS(O)(R³³)═NR³⁴, or—R³³—S(O)(R³⁴)═NR³⁵;

wherein any R³⁰/R³¹ pair attached to the same atom, together with saidatom to which they are attached, can form a ₃₋₆cyclic that can includeone or more heteroatoms selected from O, NR³⁸, or S(O₀₋₂);

each R³³, R³⁴, and R³⁵ is independently H or C₁₋₃aliphatic, eachindependently optionally substituted by one or more halo, —CN, —OR³⁶,—NR³⁶R³⁷, —C(O)R³⁶, —C(O)OR³⁶, —C(O)NR³⁶, or —OC(O)R³⁶;

wherein any R³³/R³⁴ pair attached to the same atom, together with saidatom to which they are attached, can form a ₃₋₆cyclic that can includeone or more heteroatoms selected from O, NR³⁹, or S(O₀₋₂);

each R³⁶, R³⁷, R³⁸, and R³⁹ is independently H or C₁₋₃aliphatic.

The invention includes a subgenus 5 of subgenus 4, and its salts,wherein:

R⁸ is independently halo, nitro, —CN, —OR³¹, —NR³¹R³², —C(O)R³¹,—C(O)OR³¹, C(O)NR³¹R³², —SR³¹, —R³¹, —NR³³C(O)NR³¹R³², —OC(O)R³¹,—NR³³C(O)R³¹, —NR³³C(O)OR³¹, OC(O)NR³¹R³², —C(O)—C(O)OR³¹, —S(O₁₋₂)R³¹,—S(O₁₋₂)NR³¹R³², —NR³³S(O₁₋₂)R³¹, —NR³³S(O₁₋₂)NR³¹R³², or—OS(O₁₋₂)NR³¹R³²;

in the case of a non-aromatic moiety, an R⁸ can also include oxo;

each R³¹, R³², and R³³ is independently H or C₁₋₃aliphatic.

The invention includes a subgenus 6 of Formula I or of subgenera 1-5,and its salts, wherein: A₁ is C(R⁴).

The invention includes a subgenus 7 of Formula I or of subgenera 1-5,and its salts, wherein: A₁ is N.

The invention includes a subgenus 8 of Formula I or of subgenera 1-7,and its salts, wherein: A₂ is C(O).

The invention includes a subgenus 9 of Formula I or of subgenera 1-8,and its salts, wherein: A₂ is C(H)((R)—R⁵), wherein R⁵ is C₁₋₃aliphaticoptionally substituted by one halo, —OH, —OC₁₋₃aliphatic, or —NR⁴⁰R⁴¹;and each R⁴⁰ and R⁴¹ is independently H or C₁₋₃aliphatic.

The invention includes a subgenus 10 of Formula I or of subgenera 1-9,and its salts, wherein:

R² is phenyl optionally substituted by 1-3 independent R²⁰, or R² isC₃₋₈aliphatic containing at least one cyclic or branched moiety,optionally interrupted by 1-2 heteroatoms, and optionally substituted by1-3 independent R²⁰;

each R²⁰ is independently —R²², halo, —OR²²;

R²² is H or C₁₋₃aliphatic, optionally substituted by 1-3 halo,—OC₁₋₃aliphatic.

The invention includes a subgenus 11 of Formula I or of subgenera 1-10,and its salts, wherein:

R³ is phenyl or ₆heteroaryl, either being optionally fused to ₅₋₆cyclicand optionally substituted by one or more R⁸;

each R⁸ is independently halo, —CN, —OR³¹, —NR³¹R³², —C(O)R³¹,—C(O)OR³², —C(O)NR³¹R³², —R³¹, or —OC(O)R³¹, or in the case of anon-aromatic moiety, an R⁸ can also include oxo;

each R³¹ and R³² is independently H or C₁₋₃aliphatic.

The invention includes a subgenus 12 of Formula I or of subgenera 1-11,and its salts, wherein:

R¹ is phenyl or pyridyl, either of which is optionally substituted by1-3 R⁷;

each R⁷ is independently halo, nitro, —CN, —OR¹⁰, —R¹⁰, —SR, —NR¹⁰R¹¹,—C(O)R¹⁰, —C(O)OR¹⁰, —C(O)NR¹⁰R¹¹, —NR¹⁰C(O)R¹¹, —SO₂NR¹⁰R¹¹,—NR¹⁰SO₂R¹¹, —NR¹⁰C(O)NR¹¹, or —SO₂R¹⁰;

each R¹⁰ and R¹¹ is independently H or C₁₋₃aliphatic, each independentlyoptionally substituted by one or more halo, oxo, —CN, —OR¹³, or —R¹⁴;

wherein any R¹⁰/R¹¹ pair attached to the same atom, together with saidatom to which they are attached, can form a ₃₋₆cyclic that can includeone heteroatom selected from O, —NR¹⁸, or S(O₀₋₂);

each R¹³, R¹⁴ and R¹⁸ is independently H or C₁₋₃aliphatic.

The invention includes a subgenus 13 of Formula I, and its salts,wherein:

A₁ is N; A₂ is CH((R)-methyl);

R¹ is phenyl or pyridyl, either of which is optionally substituted by1-2 independent halo, —CN, —CH₃, or —OCH₃;

R² is C₃₋₆aliphatic selected from branched and cyclic aliphaticoptionally interrupted by 1-2 heteroatoms, and optionally substituted by1-2 independent halo, —CH₃, or —OCH₃;

R³ is selected from:

wherein each A₃-A₆ is independently CH or N;

A₇ is CH₂, O, or S;

-   -   and wherein either of the above is optionally substituted by 1-3        independent halo, —CH₃, or —OCH₃ groups.

The invention includes a subgenus 14 of Formula I or of subgenera 1-12,and its salts, having the formula:

wherein R⁵ is C₁₋₃aliphatic.

The invention includes a subgenus 15 of subgenus 14, and its salts,wherein: R⁵ is methyl.

Each variable definition above includes any subset thereof and thecompounds of Formula I include any combination of such variables orvariable subsets.

In some aspects, the invention includes any of the compound examplesherein and pharmaceutically acceptable salts thereof.

The invention includes the compound or salt of the invention, which ispresent as a material that is substantially stereochemically pure.

The invention includes the compounds and salts thereof per se, and theirphysical forms, preparation of the compounds, useful intermediates, andpharmaceutical compositions and formulations thereof.

The compounds of the invention and the term “compound” in the claimsinclude any pharmaceutically acceptable salts or solvates, and anyamorphous or crystal forms, or tautomers, whether or not specificallyrecited in context.

The invention includes the isomers of the compounds. Compounds may haveone or more asymmetric carbon atoms can exist as two or morestereoisomers. Where a compound of the invention contains an alkenyl oralkenylene group, geometric cis/trans (or Z/E) isomers are possible.Where the compound contains, for example, a keto or oxime group or anaromatic moiety, tautomeric isomerism (‘tautomerism’) can occur. Asingle compound may exhibit more than one type of isomerism.

The present invention includes any stereoisomers, even if notspecifically shown, individually as well as mixtures, geometric isomers,and pharmaceutically acceptable salts thereof. Where a compound orstereocenter is described or shown without definitive stereochemistry,it is to be taken to embrace all possible individual isomers,configurations, and mixtures thereof. Thus, a material sample containinga mixture of stereoisomers would be embraced by a recitation of eitherof the stereoisomers or a recitation without definitive stereochemistry.Also contemplated are any cis/trans isomers or tautomers of thecompounds described.

Included within the scope of the invention are all stereoisomers,geometric isomers and tautomeric forms of the inventive compounds,including compounds exhibiting more than one type of isomerism, andmixtures of one or more thereof.

When a tautomer of the compound of Formula (I) exists, the compound offormula (I) of the present invention includes any possible tautomers andpharmaceutically acceptable salts thereof, and mixtures thereof, exceptwhere specifically stated otherwise.

The compounds of the invention are not limited to those containing allof their atoms in their natural isotopic abundance. The presentinvention includes compounds wherein one or more hydrogen, carbon orother atoms are replaced by different isotopes thereof such as forlabeling or other purposes. Such compounds can be useful as research anddiagnostic tools in metabolism pharmacokinetic studies and in bindingassays. A recitation of a compound or an atom within a compound includesisotopologs, i.e., species wherein an atom or compound varies only withrespect to isotopic enrichment and/or in the position of isotopicenrichment. For nonlimiting example, in some cases it may be desirableto enrich one or more hydrogen atoms with deuterium (D) or to enrichcarbon with ¹³C. Other examples of isotopes suitable for inclusion inthe compounds of the invention include isotopes of hydrogen, chlorine,fluorine, iodine, nitrogen, oxygen, phosphorus, and sulfur. Certainisotopically-labeled compounds of the invention may be useful in drugand/or substrate tissue distribution studies. Substitution with heavierisotopes such as deuterium may afford certain therapeutic advantagesresulting from greater metabolic stability, for example, increased invivo half-life or reduced dosage requirements, and hence may bepreferred in some circumstances. Substitution with positron emittingisotopes may be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Further, the compounds may be amorphous or may exist or be prepared invarious crystal forms or polymorphs, including solvates and hydrates.The invention includes any such forms provided herein, at any puritylevel. A recitation of a compound per se means the compound regardlessof any unspecified stereochemistry, physical form and whether or notassociated with solvent or water.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when the solvent is water. Pharmaceuticallyacceptable solvates in accordance with the invention include hydratesand solvates wherein the solvent of crystallization may be isotopicallysubstituted, e.g., D₂O, d6-acetone, d6-DMSO.

Also included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionized, partially ionized, or non-ionized.

The invention includes prodrugs of compounds of the invention which may,when administered to a patient, be converted into the inventivecompounds, for example, by hydrolytic cleavage. Prodrugs in accordancewith the invention can, for example, be produced by replacingappropriate functionalities present in the inventive compounds withcertain moieties known to those skilled in the art as ‘pro-moieties’ asknown in the art. Particularly favored derivatives and prodrugs of theinvention are those that increase the bioavailability of the compoundswhen such compounds are administered to a patient, enhance delivery ofthe parent compound to a given biological compartment, increasesolubility to allow administration by injection, alter metabolism oralter rate of excretion.

A pharmaceutically acceptable salt of the inventive compounds can bereadily prepared by mixing together solutions of the compound and thedesired acid or base, as appropriate. The salt may precipitate fromsolution and be collected by filtration or may be recovered byevaporation of the solvent. The degree of ionization in the salt mayvary from completely ionized to almost non-ionized.

Compounds that are basic are capable of forming a wide variety of saltswith various inorganic and organic acids. The acids that can be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form acceptable acid addition salts. When thecompound of the present invention is basic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicacids, including inorganic and organic acids. Such acids include, forexample, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Othersalts are aspartate, besylate, bicarbonate/carbonate,bisulphate/sulfate, borate, camsylate, edisylate, gluceptate,glucuronate, hexafluorophosphate, hibenzate, hydrobromide/bromide,hydroiodide/iodide, malonate, methylsulfate, naphthylate, 2-napsylate,nicotinate, orotate, oxalate, palmitate, phosphate/hydrogen,phosphate/dihydrogen, phosphate, saccharate, stearate, tartrate,tosylate, and trifluoroacetate.

When the compound of the present invention is acidic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablebases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Salts derived frompharmaceutically acceptable organic bases include salts of primary,secondary, and tertiary amines, as well as cyclic amines and substitutedamines such as naturally occurring and synthesized substituted amines.Other pharmaceutically acceptable organic bases from which salts can beformed include ion exchange resins such as, for example, arginine,betaine, caffeine, choline, N′,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. Other examples includebenzathine, diolamine, glycine, meglumine, and olamine.

Preparation

In some aspects, the invention includes the intermediates, examples, andsynthetic methods described herein in all of their embodiments.

The compounds of the Formula I may be prepared by the methods describedbelow, together with synthetic methods known in the art of organicchemistry, or modifications and derivatizations that are familiar tothose of ordinary skill in the art. The starting materials used hereinare commercially available or may be prepared by routine methods knownin the art [such as those methods disclosed in standard reference bookssuch as the Compendium of Organic Synthetic Methods, Vol. I-VI(Wiley-Interscience); or the Comprehensive Organic Transformations, byR. C. Larock (Wiley-Interscience)]. Preferred methods include, but arenot limited to, those described below.

During any of the following synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups, such as those described in T. W. Greene, ProtectiveGroups in Organic Chemistry, John Wiley & Sons (1981); T. W. Greene andP. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons(1991), and T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicChemistry, John Wiley & Sons, 1999, which are hereby incorporated byreference in their entireties.

Compounds of Formula I, or their pharmaceutically acceptable salts, andthe intermediates used in the synthesis of the compounds of thisinvention can be prepared according to the reaction schemes discussedhereinbelow and the general skill in the art. Unless otherwiseindicated, the substituents in the schemes are defined as above.Isolation and purification of the products is accomplished by standardprocedures, which are known to a chemist of ordinary skill.

When a general or exemplary synthetic procedure is referred to, oneskilled in the art can readily determine the appropriate reagents, ifnot indicated, extrapolating from the general or exemplary procedures.Some of the general procedures are given as examples for preparingspecific compounds. One skilled in the art can readily adapt suchprocedures to the synthesis of other compounds. Representation of anunsubstituted position in structures shown or referred to in the generalprocedures is for convenience and does not preclude substitution asdescribed elsewhere herein. For specific groups that can be present,either as R groups in the general procedures or as optional substituentsnot shown, refer to the descriptions in the remainder of this document,including the claims, summary and detailed description.

The process to produce compounds of the present invention is preferablycarried out at about atmospheric pressure although higher or lowerpressures can be used if desired. Substantially equimolar amounts ofreactants are preferably used although higher or lower amounts can alsobe used.

General Schemes

Method A may be used to prepare compounds of Formula I-A as shown belowin Scheme 1:

where R¹, R², R³, R⁵, R⁶ are as defined previously. X is halogen such asCl, Br, I or other suitable leaving groups.

In a typical preparation of a compound of Formula I-A, a compound ofFormula II-A is reacted with R³—NH₂ in a suitable solvent. Suitablesolvents include, but are not limited to, ethers such as THF, glyme, andthe like; toluene, benzene and the like, DMF, DMSO, MeCN; alcohols suchas MeOH, EtOH, IPA, trifluoroethanol, butanol and the like; if desired,mixtures of these solvents are used, however, the preferred solvents aretrifluoroethanol or butanol. A certain amount of Brønsted acid(catalytic amount, stoichiometric amount or excessive amount) may beadded to the reaction mixture to facilitate the reaction. SuitableBrønsted acids include, but are not limited to, HCl, TFA and the like.The above process may be carried out at temperatures between about −78°C. and about 150° C. Preferably, the reaction is carried out betweenabout 80° C. and about 120° C. The above process is preferably carriedout in a sealed reaction vessel such as, but not limited to, a thickwalled glass reaction vessel. The above process could also be carriedout in a microwave reactor under appropriate microwave reactionconditions.

Alternatively, compounds of Formula I-A could also be prepared byreacting a compound of Formula II-A (X is halogen such as Cl, Br, I orOTf) with R³—NH₂ in a suitable solvent under transition metal catalysis(for example, Buchwald-Hartwig coupling or the like). Suitable solventsinclude, but are not limited to, ethers such as THF, glyme, and thelike; toluene, benzene and the like, DMF. If desired, mixtures of thesesolvents are used, however, the preferred solvents are DMF or toluene.Suitable transition metal catalysts include, but are not limited toPd(PPh₃)₄, Pd(OAc)₂, Pd(dppf)Cl₂, Pd₂(dba)₃ and the like. Additionalligands may be added to the reaction mixture. Suitable ligands include,but are not limited to 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) and thelike. Preferably, the reaction is carried out in the presence of a basesuch as, but not limited to, Cs₂CO₃, NaOtBu and the like. The aboveprocess may be carried out at temperatures between about −78° C. andabout 150° C. Preferably, the reaction is carried out between about 80°C. and about 120° C. The above process is preferably carried out in asealed reaction vessel such as, but not limited to, a thick walled glassreaction vessel. The above process could also be carried out in amicrowave reactor under appropriate microwave reaction conditions.

Compounds of Formula II-A of Scheme 1 may be prepared as shown below inScheme 2.

where R¹, R², R⁵, R⁶ are as defined previously. X is halogen such as Cl,Br, I or other suitable leaving groups.

In a typical preparation of a compound of Formula II-A, an intermediateof Formula III-A1 is reacted with R¹—B(OH)₂ in a suitable solvent at asuitable reaction temperature in the presence of a metal couplingreagent and a base. Suitable solvents include, but are not limited to,ethers such as THF, glyme, and the like; toluene, benzene and the like,DMF, and chlorinated solvents such as DCM, 1,2-dichloroethane (DCE) orCHCl₃ and the like. If desired, mixtures of these solvents are used. Thepreferred solvents are DCM or DCE. The above process may be carried outat temperatures between about −78° C. and about 120° C. Preferably, thereaction is carried out between about 20° C. and about 50° C. Suitablemetal coupling reagents include, but are not limited to, Copper(II)reagents such as Cu(OAc)₂; suitable bases include, but are not limitedto, TEA, DIPEA. Molecular sieves may also be added to the reactionmixture to facilitate the reaction.

Alternatively, compounds of Formula II-A of Scheme 1 could also beprepared from an intermediate of Formula III-A2 as shown in Scheme 3.

where R¹, R², R⁵, R⁶ are as defined previously. X and XI are eachindependently halogens such as Cl, Br, I or other suitable leavinggroups.

In a typical preparation of a compound of Formula II-A, an intermediateof Formula III-A2 is reacted with R²—XI in a suitable solvent at asuitable reaction temperature in the presence of a base. Suitablesolvents include, but are not limited to, ethers such as THF, glyme, andthe like; DMF, DMSO. If desired, mixtures of these solvents are used.The preferred solvent is DMF. The above process may be carried out attemperatures between about −78° C. and about 150° C. Preferably, thereaction is carried out between about 20° C. and about 120° C. Suitablebases include, but are not limited to, NaH, NaOtBu and the like.

It would be appreciated by those skilled in the art that compounds ofFormula II-A of Scheme 3 could also be prepared by other methods whichinclude, but are not limited to, a reductive amination reaction betweenan intermediate of Formula III-A2 and an appropriate aldehyde or ketone,or a transition metal catalyzed coupling reaction between anintermediate of Formula III-A2 and R²—XI (for example, Buchwald-Hartwigcoupling or the like).

Compounds of Formula III-A1 of Scheme 2 may be prepared as shown belowin Scheme 4.

where R², R⁵, R⁶ are as defined previously. X is halogen such as Cl, Br,I or other suitable leaving groups, XA is an alkyl group such as methyl,ethyl and the like.

In a typical preparation of a compound of Formula III-A1, anintermediate of Formula IV-A1 is reacted with a reducing reagent.Suitable solvents include, but are not limited to, alcohols such asMeOH, EtOH and the like. An acid is added to the reaction mixture.Suitable acids include, but are not limited to, HCl, acetic acid (AcOH)and the like. The reaction may also be carried out in neat AcOH withoutany other solvent. The above process may be carried out at temperaturesbetween about −78° C. and about 150° C. Preferably, the reaction iscarried out between about 50° C. and about 120° C. Suitable reducingagents include, but are not limited to, iron powder.

Compounds of Formula IV-A1 of Scheme 4 may be prepared as shown below inScheme 5.

where R², R⁵, R⁶ are as defined previously. X, XI are each independentlyhalogens such as Cl, Br, I or other suitable leaving groups, XA is analkyl group such as methyl, ethyl and the like. The skilled artisan willrecognize that a larger number of compounds V-A1, including cycliccompounds such as where R² and R⁵ are linked, are commercially availableor otherwise accessible.

In a typical preparation of a compound of Formula IV-A1, an intermediateof Formula V-A1 (in free base or a salt form) is reacted with anintermediate of Formula VI. Suitable solvents include, but are notlimited to, water, ethers such as THF, glyme, and the like; toluene,benzene and the like, DMF, DMSO, MeCN. If desired, mixtures of thesesolvents are used, however, the preferred solvents are water and ether.A base may be added to the reaction to facilitate the reaction. Suitablebases include, but are not limited to, Cs₂CO₃, K₂CO₃, and the like. Theabove process may be carried out at temperatures between about −78° C.and about 100° C. Preferably, the reaction is carried out between about−20° C. and about 50° C.

Compounds of Formula V-A1 of Scheme 5 may be prepared as shown below inScheme 6.

where R², R⁵, R⁶ are as defined previously. X is a halogen such as Cl,Br, I or other suitable leaving groups, XA is an alkyl group such asmethyl, ethyl and the like.

In a typical preparation of a compound of Formula V-A1, an intermediateof Formula VII-A1 is reacted with an intermediate of Formula VIII (infree base or a salt form). Suitable solvents include, but are notlimited to, water, ethers such as THF, glyme, and the like; toluene,benzene and the like, DMF, DMSO, MeCN, ethyl acetate. If desired,mixtures of these solvents are used. The preferred solvent is DMF. Abase may be added to facilitate the reaction. Suitable bases include,but are not limited to, Cs₂CO₃, K₂CO₃, and the like. The above processmay be carried out at temperatures between about −78° C. and about 120°C. Preferably, the reaction is carried out between about −20° C. andabout 100° C.

It would be appreciated by those skilled in the art that compounds ofFormula V-A1 of Scheme 5 could also be prepared by other methods whichinclude, but are not limited to, a reductive amination reaction betweenan intermediate of Formula IX-A1 and an appropriate aldehyde or ketone,as shown in Scheme 7.

where R², R⁵, R⁶ are as defined previously. XA is an alkyl group such asmethyl, ethyl and the like. The skilled artisan will recognize that alarger number of compounds IX-A1, including cyclic compounds such aswhere R⁵ and R⁶ are linked, are commercially available or otherwiseaccessible.

In a typical preparation of a compound of Formula V-A1, an intermediateof Formula IX-A1 (in free base or a salt form) is reacted with anappropriate aldehyde or ketone in the presence of a reducing reagent.Suitable solvents include, but are not limited to, water, ethers such asTHF, glyme, and the like; toluene, benzene and the like, DMF, MeCN,ethyl acetate, alcohols such as MeOH, EtOH, and the like. If desired,mixtures of these solvents are used. The preferred solvents arealcohols. The suitable reducing reagents include, but are not limited toNaBH₄, NaBH(OAc)₃, NaBH₃CN, and the like. The above process may becarried out at temperatures between about −78° C. and about 100° C.Preferably, the reaction is carried out between about −20° C. and about50° C.

Compounds of Formula III-A2 of Scheme 3 may be prepared as shown belowin Scheme 8.

where R¹, R⁵, R⁶ are as defined previously. X is an halogen such as Cl,Br, I or other suitable leaving groups.

In a typical preparation of a compound of Formula III-A2, anintermediate of Formula IV-A2 is reacted with R¹—B(OH)₂ according toreaction conditions similar to the synthesis of compounds of FormulaII-A from compounds of Formula III-A1 described above.

Compounds of Formula IV-A2 of Scheme 8 may be prepared as shown below inScheme 9.

where R⁵, R⁶ are as defined previously. X is an halogen such as Cl, Br,I or other suitable leaving groups. XA is an alkyl group such as methyl,ethyl and the like.

In a typical preparation of a compound of Formula IV-A2, an intermediateof Formula V-A2 is reacted with an reducing reagent, according toreaction conditions similar to the synthesis of compounds of FormulaIII-A1 from compounds of Formula IV-A1 described above.

Compounds of Formula V-A2 of Scheme 9 may be prepared as shown below inScheme 10.

where R⁵, R⁶ are as defined previously. X, XI are each independentlyhalogens such as Cl, Br, I or other suitable leaving groups, XA is analkyl group such as methyl, ethyl and the like.

In a typical preparation of a compound of Formula V-A2, an intermediateof Formula IX-A1 (in free base or a salt form) is reacted with anintermediate of Formula VI, according to reaction conditions similar tothe synthesis of compounds of Formula IV-A1 from compounds of FormulaV-A1 described above.

Method B may be used to prepare compounds of Formula I-B as shown belowin Scheme 11:

where R¹, R², R³, R⁴, R⁵, R⁶ are as defined previously. X is halogensuch as CI, Br, I or OTf.

In a typical preparation of a compound of Formula I-B, a compound ofFormula II-B is reacted with R³—NH₂ in a suitable solvent undertransition metal catalysis (for example, Buchwald-Hartwig coupling orthe like). Suitable solvents include, but are not limited to, etherssuch as THF, glyme, and the like; toluene, benzene and the like, DMF,DMSO. If desired, mixtures of these solvents are used, however, thepreferred solvents are DMF or toluene. Suitable transition metalcatalysts include, but are not limited to Pd(PPh₃)₄, Pd(OAc)₂,Pd(dppf)Cl₂, Pd₂(dba)₃ and the like. Additional ligands may be added tothe reaction mixture. Suitable ligands include, but are not limited toBINAP, SPhos, XPhos and the like. Preferably, the reaction is carriedout in presence of a base such as Cs₂CO₃, NaOtBu and the like. The aboveprocess may be carried out at temperatures between about −78° C. andabout 150° C. Preferably, the reaction is carried out between about 80°C. and about 120° C. The above process is preferably carried out in asealed reaction vessel such as, but not limited to, a thick walled glassreaction vessel. The above process could also be carried out in amicrowave reactor under appropriate microwave reaction conditions.

Compounds of Formula II-B of Scheme 11 may be prepared as shown below inScheme 12.

where R¹, R², R⁴, R⁵, R⁶ are as defined previously. X is halogen such asCI, Br, I or OTf.

In a typical preparation of a compound of Formula II-B, an intermediateof Formula III-B is reacted with R¹—B(OH)₂, according to reactionconditions similar to the synthesis of compounds of Formula II-A fromcompounds of Formula III-A1 described above.

Compounds of Formula III-B of Scheme 12 may be prepared as shown belowin Scheme 13.

where R², R⁴, R⁵, R⁶ are as defined previously. X is a halogen such asCI, Br, I or OTf.

XI is halogen such as CI, Br, I or other suitable leaving groups.

In a typical preparation of a compound of Formula III-B, an intermediateof Formula IV-B is treated with a base in a suitable solvent at asuitable reaction temperature. Suitable solvents include, but are notlimited to, ethers such as THF, glyme, and the like; toluene, benzeneand the like, DMF, DMSO, MeCN and chlorinated solvents such as DCM, DCEor CHCl₃ and the like. If desired, mixtures of these solvents are used.The preferred solvent is DMF. The above process may be carried out attemperatures between about −78° C. and about 150° C. Preferably, thereaction is carried out between about 50° C. and about 130° C. Suitablebases include, but are not limited to, Cs₂CO₃, K₃PO₄, NaOtBu and thelike.

Compounds of Formula IV-B of Scheme 13 may be prepared as shown below inScheme 14.

where R², R⁴, R⁵, R⁶ are as defined previously. X is a halogen such asCl, Br, I or OTf. XI, XII are each independently halogens such as CI,Br, I or other suitable leaving groups.

In a typical preparation of a compound of Formula IV-B, an intermediateof Formula V-B is reacted with R₂—NH₂ (in free base or a salt form).Suitable solvents include, but are not limited to, water, ethers such asTHF, glyme, and the like; toluene, benzene and the like, DMF, DMSO,MeCN, ethyl acetate; chlorinated solvents such as DCM, DCE or CHCl₃ andthe like. If desired, mixtures of these solvents are used. The preferredsolvent is DMF. A base may be used to facilitate the reaction. Suitablebases include, but are not limited to, Cs₂CO₃, K₂CO₃, and the like. Theabove process may be carried out at temperatures between about −78° C.and about 120° C. Preferably, the reaction is carried out between about−20° C. and about 100° C.

Compounds of Formula V-B of Scheme 14 may be prepared as shown below inScheme 15.

where R⁴, R⁵, R⁶ are as defined previously. X is a halogen such as Cl,Br, I or OTf. XI, XII, XIII are each independently halogens such as Cl,Br, I or other suitable leaving groups.

In a typical preparation of a compound of Formula V-B, an intermediateof Formula VI-B is reacted with intermediate of Formula VII-B. Suitablesolvents include, but are not limited to, ethers such as THF, glyme, andthe like; toluene, benzene and the like, DMF, DMSO, MeCN, ethyl acetate;chlorinated solvents such as DCM, DCE or CHCl₃ and the like. If desired,mixtures of these solvents are used. The preferred solvent is DMF. Abase may be used to facilitate the reaction. Suitable bases include, butare not limited to, TEA, DIPEA and the like. The above process may becarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction is carried out between about −20° C. and about100° C.

It would be appreciated by those skilled in the art that compounds ofFormula V-B of Scheme 15 could also be prepared by other methods whichinclude, but are not limited to, a amide coupling reaction between anintermediate of Formula VI-B and an appropriate acid in the presence ofa amide coupling reagent. The suitable reaction conditions for amidecouplings may be found in Larock, R. C. Comprehensive OrganicTransformations, 2^(nd) ed.; Wiley and Sons: New York, 1999, or in othersimilar literature sources.

It would be appreciated by those skilled in the art that compounds ofFormula IV-B of Scheme 14 could also be prepared by other methods whichinclude, but are not limited to, a reductive amination reaction betweenan intermediate of Formula VIII-B and an appropriate aldehyde or ketone,as shown in Scheme 16.

where R², R⁴, R⁵, R⁶ are as defined previously. X is a halogen such asCI, Br, I or OTf., XI is halogen such as CI, Br, I or other suitableleaving groups.

In a typical preparation of a compound of Formula IV-B, an intermediateof Formula VIII-B (in free base or a salt form) is reacted with anappropriate aldehyde or ketone in the presence of a reducing reagent.Suitable solvents include, but are not limited to, water, ethers such asTHF, glyme, and the like; toluene, benzene and the like, DMF, DMSO,MeCN, ethyl acetate, alcohols such as MeOH, EtOH and the like. Ifdesired, mixtures of these solvents are used. The preferred solvents arealcohols. The suitable reducing reagents include, but are not limited toNaBH₄, NaBH(OAc)₃, NaBH₃CN, and the like. The above process may becarried out at temperatures between about −78° C. and about 100° C.Preferably, the reaction is carried out between about −20° C. and about50° C.

It would be appreciated by those skilled in the art that compounds ofFormula VIII-B of Scheme 16 could be prepared by methods which include,but are not limited to, a amide coupling reaction between anintermediate of Formula VI-B and an appropriate acid in the presence ofa amide coupling reagent. The suitable reaction conditions for amidecouplings can be found in Larock, R. C. Comprehensive OrganicTransformations, 2^(nd) ed.; Wiley and Sons: New York, 1999, or in othersimilar literature sources.

Method C may be used to prepare compounds of Formula I-C as shown belowin Scheme 17:

where R¹, R², R³ are as defined previously. X is halogen such as CI, Br,I or other suitable leaving groups.

In a typical preparation of compounds of Formula I-C, compound ofFormula II-C is reacted with R³—NH₂, according to reaction conditionssimilar to the synthesis of compounds of Formula I-A from compounds ofFormula II-A described above.

The compounds of Formula II-C of Scheme 17 may be prepared as shownbelow in Scheme 18.

where R¹, R² are as defined previously. X is halogen such as CI, Br, Ior other suitable leaving groups.

In a typical preparation of a compound of Formula II-C, an intermediateof Formula III-C is reacted with R¹—B(OH)₂, according to reactionconditions similar to the synthesis of compounds of Formula II-A fromcompounds of Formula III-A1 described above.

The compounds of Formula III-C of Scheme 18 may be prepared as shownbelow in Scheme 19.

where R² is as defined previously. X, XI are each independently halogenssuch as CI, Br, I or other suitable leaving groups, XA is an alkyl groupsuch as methyl, ethyl and the like.

In a typical preparation of a compound of Formula III-C, an intermediateof Formula IV-C is reacted with compound IV-C1 in a suitable solvent ata suitable reaction temperature in the presence of a base. Suitablesolvents include, but are not limited to, ethers such as THF, glyme, andthe like; toluene, benzene and the like, DMF, DMSO, MeCN and chlorinatedsolvents such as DCM, DCE or CHCl₃ and the like. If desired, mixtures ofthese solvents are used or no solvent is used. The preferred solvent istoluene. The above process may be carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction is carried outbetween about 20° C. and about 50° C. Suitable bases include, but arenot limited to, TEA, DIPEA.

The compounds of Formula IV-C of Scheme 19 may be prepared as shownbelow in Scheme 20.

where R² is as defined previously. X is halogen such as CI, Br, I orother suitable leaving groups.

In a typical preparation of a compound of Formula IV-C, an intermediateof Formula V-C is reacted with iron as reducing reagent. Suitablesolvents include, but are not limited to, alcohols such as MeOH, EtOHand the like. An acid is added to the reaction mixture. Suitable acidsinclude, but are not limited to, HCl, Acetic acid (AcOH) and the like.The above process may be carried out at temperatures between about −78°C. and about 150° C. Preferably, the reaction is carried out betweenabout 50° C. and about 120° C.

It would be appreciated by those skilled in the art that the reductionreaction in Scheme 24 could also be achieved by various other methodsdescribed in literature using various reducing reagents such as, but notlimited to, SnCl₂, H₂ (hydrogenation).

The compounds of Formula V-C of Scheme 20 may be prepared as shown belowin Scheme 21.

where R² is as defined previously. X, XI are each independently halogenssuch as CI, Br, I or other suitable leaving groups.

In a typical preparation of a compound of Formula V-C, an intermediateof Formula VI is reacted with R²—NH₂ (in free base or a salt form).Suitable solvents include, but are not limited to, water, ethers such asTHF, glyme, and the like; toluene, benzene and the like, DMF, DMSO,MeCN. If desired, mixtures of these solvents are used, however, thepreferred solvents are mixture of water and ether. A base may be addedto the reaction to facilitate the reaction. Suitable bases include, butare not limited to, Cs₂CO₃, K₂CO₃, and the like. The above process maybe carried out at temperatures between about −78° C. and about 100° C.Preferably, the reaction is carried out between about −20° C. and about50° C.

Method D may be used to prepare compounds of Formula I-D as shown belowin Scheme 22:

where R¹, R², R³, R⁴ are as defined previously for compound of FormulaI. X is halogen such as CI, Br, I or OTf.

In a typical preparation of a compound of Formula I-D, a compound ofFormula II-D is reacted with R³—NH₂ in a suitable solvent undertransition metal catalysis (for example, Buchwald-Hartwig coupling orthe like). Suitable solvents for use in the above process include, butare not limited to, ethers such as THF, glyme, and the like; toluene,benzene and the like, DMF, DMSO. If desired, mixtures of these solventsare used. Suitable transition metal catalyst for use in the aboveprocess include, but are not limited to Pd(PPh₃)₄, Pd(OAc)₂,Pd(dppf)Cl₂, Pd₂(dba)₃ and the like. Additional ligands may be added tothe reaction mixture. Suitable ligands for use in the above processinclude, but are not limited to2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) and thelike. Preferably, the reaction is carried out in presence of a base suchas Cs₂CO₃, NaOtBu and the like. The above process is carried out attemperatures between about −78° C. and about 150° C. Preferably, thereaction is carried out between 60° C. and about 120° C. The aboveprocess is preferably carried out in a sealed reaction vessel such as,but not limited to, a thick walled glass reaction vessel. The aboveprocess to produce compounds of the present invention could also becarried out in a microwave reactor under appropriate microwave reactionconditions.

The compounds of Formula II-D of Scheme 22 may be prepared as shownbelow in Scheme 23.

where R¹, R², R⁴ are as defined previously for compound of Formula I. Xis halogen such as CI, Br, I or OTf.

In a typical preparation of a compound of Formula II-D, an intermediateof Formula III-D is reacted with R¹—B(OH)₂, according to reactionconditions similar to the synthesis of compounds of Formula II-A fromcompounds of Formula III-A1 described above.

The compounds of Formula III-D of Scheme 23 may be prepared as shownbelow in Scheme 24.

where R², R⁴ are as defined previously for compound of Formula I. X ishalogen such as CI, Br, I or OTf. XI is halogen such as CI, Br, I orother suitable leaving groups, XA is an alkyl group such as methyl,ethyl and the like.

In a typical preparation of a compound of Formula III-D, an intermediateof Formula IV-D is reacted with compound IV-C1 in a suitable solvent ata suitable reaction temperature in the presence of a base. Suitablesolvents for use in the above process include, but are not limited to,ethers such as THF, glyme, and the like; toluene, benzene and the like,dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile (MeCN)and chlorinated solvents such as dichloromethane (DCM),1,2-dichloroethane (DCE) or chloroform (CHCl₃) and the like. If desired,mixtures of these solvents are used or no solvent is used. The aboveprocess is carried out at temperatures between about −78° C. and about120° C. Preferably, the reaction is carried out between 20° C. and about80° C. Suitable bases for use in the above process include, but are notlimited to, triethylamine (TEA), diisopropylethylamine (DIPEA).

The compounds of Formula IV-D of Scheme 24 are prepared as shown belowin Scheme 25.

where R², R⁴ are as defined previously for compound of Formula I. X ishalogen such as CI, Br, I or OTf.

In a typical preparation of a compound of Formula IV-D, an intermediateof Formula V-D is reacted with a suitable reducing reagent, according toreaction conditions similar to the synthesis of compounds of FormulaIV-C from compounds of Formula V-C described above.

The compounds of Formula V-D of Scheme 25 are prepared as shown below inScheme 26.

where R², R⁴ are as defined previously for compound of Formula I. X ishalogen such as CI, Br, I or OTf.

In a typical preparation of a compound of Formula V-D, an intermediateof Formula VI-D is reacted with an appropriate aldehyde or ketone in thepresence of a reducing reagent.

Suitable solvents for use in the above process include, but are notlimited to, water, ethers such as THF, glyme, and the like; toluene,benzene and the like, dimethylformamide (DMF), acetonitrile (MeCN),ethyl acetate, alcohols such as MeOH, EtOH, and the like. If desired,mixtures of these solvents are used. The preferred solvents arealcohols. The suitable reducing reagents for use in the above processinclude, but are not limited to NaBH₄, NaBH(OAc)₃, NaBH₃CN, and thelike. The above process is carried out at temperatures between about−78° C. and about 100° C. Preferably, the reaction is carried outbetween −20° C. and about 50° C.

EXAMPLES

Unless otherwise noted, all materials/reagents were obtained fromcommercial suppliers and used without further purification. Reactionswere monitored by thin layer chromatography (TLC) on silica gel 60 F₂₅₄(0.2 mm) precoated aluminum foil or glass-backed and visualized using UVlight. Flash chromatography (alternatively called “ISCO chromatography”)was performed using an ISCO CombiFlash Rf 4× Organic Purification Systemor equivalent with RediSep normal-phase silica gel cartridges.Preparative TLC was performed on Whatman LK6F Silica Gel 60 Å size 20×20cm plates with a thickness of 1000 μm or equivalent. Hydromatrix(=diatomaceous earth) was purchased from Varian.

¹H NMR (300 or 400 MHz) and ¹³C NMR (100.6 MHz) spectra were recorded onBruker or Varian spectrometers at RT with TMS or the residual solventpeak as the internal standard. The line positions or multiples are givenin (5) and the coupling constants (J) are given as absolute values inHertz (Hz). The multiplicities in ¹H NMR spectra are abbreviated asfollows: s (singlet), d (doublet), t (triplet), q (quartet), quint(quintet), m (multiplet), m_(c) (centered multiplet), br or broad(broadened), AA‘BB’. The signal multiplicities in ¹³C NMR spectra weredetermined using the DEPT135 experiment and are abbreviated as follows:+(CH or CH₃), −(CH₂), C_(quart) (C).

Preparative HPLC purifications (“MDP”) were performed on a Waters®Mass-Directed Purification System equipped with 2525 Binary GradientModule, 2767 Sample Manager, a Column Fluidics Organizer (CFO), 2996Photodiode Array Detector, a 515 pump for column regeneration, a reagentmanager for the makeup flow, a 515 pump for at-column-dilution, ZQ™single-quadrupole Mass Detector equipped with a Z-spray electrosprayinterface, controlled by MassLynx™ Version 4.1 with FractionLynx™software. All purification work was completed using a paralleldual-column Luna C18(2) 21×150 mm, 5 μm LC/MS system and ARW(accelerated retention window). The mobile phases were water (0.1% TFA)and acetonitrile (0.1% TFA); all reagents used were of HPLC grade. Theflow rate was 30 mL/min. After the columns, a 1:1000 LC packings flowsplitter allowed transfer of a small portion of the eluent into the UVdetector and, subsequently, a 10% portion into the ZQ MS. Theelectrospray source was set at 3.0 kV capillary voltage, 30 V conevoltage, 110° C. source temperature, 350° C. desolvation temperature,600 L/h desolvation gas flow, and 60 L/h cone gas flow. For theanalyzer, the multiplier was set at 550 for preparative tune method.

Analytical LC-MS data was collected on ZQ3, TOF, or UPLC instrumentswith a mobile phase of Acetonitrile (A) and 0.01% Formic Acid in HPLCgrade water (B).

ZQ3 is an Agilent 1100 HPLC equipped with an ESA CAD secondary detectorand Waters Micromass ZQ2000 for ionization. The system uses thefollowing conditions for either 5 or 4 min run time.

5 minute run: Xterra MS C18 column, 5 μm, 4.6×50 mm. The flow rate is1.3 mL/min, the run time is 5 min, and the gradient profiles are 0.00min 5% A, 3.00 min 90% A, 3.50 min 90% A, 4.00 min 5% A, 5.00 min 5% Afor polar_5 min; and 0.00 min 25% A, 3.00 min 99% A, 3.50 min 99% A,4.00 min 25% A, 5.00 min 25% A for nonpolar_5 min. The flow rate is 1.0mL/min, the run time is 5 min, and the gradient profiles are 0.00 min 1%A, 0.3 min 1% A, 3.00 min 90% A, 3.50 min 90% A, 4.00 min 1% A, 5.00 min1% A for vvpolar_5 min. The Waters Micromass ZQ2000 instrument utilizedelectrospray ionization in positive (ES⁺) or negative (ES⁻) mode. TheWaters Micromass ZQ2000 instrument can also utilize atmospheric pressurechemical ionization in positive (AP+) or negative (AP−) mode.

4 minute run: XTerra MS C18 column, 3.5 μm, 4.6×50 mm. The flow rate is1.0 mL/min, the run time is 4 min, and the gradient profiles are 0.00min 5% A, 2.00 min 90% A, 2.50 min 90% A, 3.00 min 5% A, 4.00 min 5% Afor polar_4 min; and 0.00 min 25% A, 2.00 min 99% A, 2.50 min 99% A,3.00 min 25% A, 4.00 min 25% A for nonpolar_4 min.

TOF is a Waters UPLC-LCT Premier system consisting of an ACQUITY UPLCequipped with an ACQUITY Sample Manager and LCT Premier XE MS forionization. It uses an ACQUITY UPLC BEH® C18 2.1×50 mm, 1.7 μm columnwith a mobile phase of Acetonitrile (A) and 0.01% formic acid in water(B). The flow rate is 0.6 mL/min, run time is 3 min, and the gradientprofile is 0.00 min 5% A, 0.2 min 5% A, 1.50 min 90% A, 2 min 90% A, 2.2min 5% A, 3 min 5% A for polar_3 min; and 0.00 min 25% A, 0.2 min 25% A,1.50 min 99% A, 2 min 99% A, 2.2 min 25% A, 3 min 25% A for nonpolar_3min. Or, the flow rate is 0.7 mL/min, run time is 2 min, and thegradient profile is 0.00 min 10% A, 1 min 90% A, 1.5 min 90% A, 1.6 min10% A, 2 min 10% A for polar_2 min; and 0.00 min 30% A, 1 min 90% A, 1.5min 90% A, 1.6 min 30% A, 2 min 30% A for nonpolar_2 min. The LCTPremier XE MS utilized electrospray ionization in positive (ES⁺) ornegative (ES⁻), as well positive (AP⁺) or negative (AP⁻) in W mode.

UPLC is an ACQUITY sample manager attached to an ACQUITY SQ detector.ACQUITY UPLC® BEH C18 1.7 μm 2.1×50 mm or 2.1×100 mm column was heatedto 60° C. with detection at 254 nm and electrospray ionization inpositive mode was used. The table below lists the mobile phase gradient(solvent A: 0.1% formic acid in water; solvent B: 0.1% formic acid inacetonitrile) and flow rate for the analytical UPLC program.

Time (min) A % B % Flow Rate (mL/min) Analytical Method: Purity_2 min(column: 2.1 × 50 mm) 0.00 95.0 5.0 1.00 1.50 1.0 99.0 1.00 1.80 1.099.0 1.00 2.00 95.0 5.0 1.00 Analytical Method: Analytical_2 min(column: 2.1 × 100 mm) 0.00 85.0 15.0 0.80 1.50 1.0 99.0 0.80 1.80 1.099.0 0.80 2.00 85.0 15.0 0.80

Unless otherwise noted, all HPLC retention times are reported using theZQ3 polar_5 min gradient method.

All melting points were determined with a Mel-Temp II apparatus and areuncorrected. Elemental analyses were obtained by Atlantic Microlab,Inc., Norcross, Ga. Optical rotations were recorded on a Perkin-Elmer241 polarimeter at room temperature.

Supercritical fluid chromatography (SFC, Thar/Waters) equipped with aWaters ZQ MS for ionization, is used for compound purifications,including separation of cis- and trans-isomers. Following conditions orsimilar conditions are followed for separation of cis- andtrans-isomers:

SFC Analytical Chromatographic Conditions:

Column: CHIRALPACK IA 4.6×100 mm, 5u

Modifier: 0.2% IPAmine in MeOH

Flow Rate: 4 mL/min

Gradient: 10% to 60% modifier in 5 min

SFC Semi-Prep Chromatographic Conditions:

Column: CHIRALPACK IA 21×250 mm, 5u

Modifier: 0.2% IPAmine in MeOH

Flow Rate: 30 mL/min

Gradient: 35% to 50% modifier in 5 min followed by 50% isocratic.

Synthesis of Examples 1-12

Example 12-(1H-indazol-5-ylamino)-7-methyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one

Step e: A mixture of2-chloro-7-methyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one

(172 mg, 0.50 mmol), 5-aminoindazole (100 mg, 0.75 mmol),trifluoroacetic acid (2.0 mmol) in trifluoroethanol (2.0 ml) was heatedin a microwave reactor at 125° C. for 30 minutes. The reaction mixturewas diluted with ethyl acetate (50 ml) and washed with aqueous saturatedsodium bicarbonate, dried (Na₂SO₄) and evaporated. The residue waspurified by column chromatography on silica gel using 2% methanol indichloromethane as eluent to give the titled product. (yield: 54%).¹HNMR (300 MHz, CDCl₃): δ 0.96-1.0 (m, 6H), 1.54 (d, J=6.9 Hz, 3H),1.62-1.67 (m, 3H), 3.10-3.16 (m, 1H), 4.15-4.22 (m, 1H), 4.36 (q, J=6.6Hz, 1H), 7.03 (s, 1H), 7.23-7.54 (m, 8H), 7.98 (s, 1H). 8.08 (s, 1H) and10.03 (s, 1H). MS(ES⁺): m/z=442.00 [MH⁺]. HPLC: t_(R)=3.09 (ZQ3, Polar_5min).

Step d:2-Chloro-7-methyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one

To a stirred solution of2-chloro-7-methyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one (2.0g, 7.4 mmol) in dichloromethane (100 mL) was added triethylamine (10.4ml, 74 mmol), cupric acetate (2.70 g, 14.8 mmol) and phenylboronic acid(1.81 g, 14.8 mmol) followed by 4 Å molecular sieves (3.0 g). Thereaction mixture was stirred for 48 h at room temperature with an airballoon. The mixture was then filtered over celite. The filtrate waswashed with aqueous saturated sodium bicarbonate (2×50 ml), dried overanhydrous sodium sulfate and evaporated. The residue was purified bycolumn chromatography on silica gel using 2% methanol in dichloromethaneas eluent to give the titled product. (yield: 39%). ¹HNMR (300 MHz,CDCl₃): δ 0.91-1.01 (m, 6H), 1.49-1.75 (m, 6H), 3.12-3.20 (m, 1H),4.18-4.21 (m, 1H), 4.30-4.45 (m, 1H), 7.10 (s, 1H), 7.20-7.39 (m, 2H),7.42-7.65 (m, 3H).

Step c:2-Chloro-7-methyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one

A mixture of methylN-(2-chloro-5-nitropyrimidin-4-yl)-N-(3-methylbutyl)alaninate (16.2 g,49 mmol), iron powder (6.9 g, 123 mmol) and glacial acetic acid (165 mL)was heated at 60° C. for 2 h. The reaction mixture was then filteredwhile hot over celite and washed with hot acetic acid (40 mL) followedby ethyl acetate (250 mL). The filtrate after evaporation was taken upin ethyl acetate and washed two times with aq. saturated sodiumbicarbonate solution followed by brine. It was dried over sodium sulfateand evaporated. The residue was triturated with hot isopropyl ether togive titled product (yield: 61%). ¹HNMR (300 MHz, CDCl₃): δ 0.92-1.01(m, 7H), 1.43-1.75 (m, 5H), 3.01-3.20 (m, 1H), 4.10-4.25 (m, 2H), 7.63(s, 1H), 9.13 (s, 1H).

Step b: MethylN-(2-chloro-5-nitropyrimidin-4-yl)-N-(3-methylbutyl)alaninate

A solution of 2,4-dichloro-5-nitropyrimidine (27.8 g, 144 mmol) in ether(350 mL) was cooled to −10° C. and was treated with methylN-(3-methylbutyl)alaninate (20.8 g, 120 mmol). A solution of potassiumbicarbonate (25.0 g in 180 mL water) was added drop wise maintaining thetemperature below 0° C. Reaction mixture was then allowed to come toroom temperature and stirred for 2 h. Ether layer was separated, the aq.layer was extracted with ether (3×100 mL). Combined ether solution waswashed with brine, dried over anhydrous sodium sulfate and evaporated.The residue was purified by flash chromatography on silica gel usingethyl acetate-hexane mixture (v:v=5:95) to give titled product (yield:51%). ¹HNMR (300 MHz, CDCl₃): δ 0.90-1.01 (m, 6H), 1.40-1.61 (m, 6H),3.10-3.21 (m, 1H), 3.39-3.45 (m, 1H), 3.78 (s, 3H), 4.41-4.50 (s, 1H),8.71 (s, 1H).

Step a: Methyl N-(3-methylbutyl)alaninate

A suspension of DL-alanine methyl ester hydrochloride (41.8 g, 300 mmol)in dry dichloromethane (650 mL) was treated with potassium acetate (30.0g, 306 mmol) and the reaction mixture stirred for ten minutes at rt.Reaction flask was then cooled to 10° C. and treated with3-methylbutanal (25.8 g, 300 mmol). This was followed by the addition ofsodium triacetoxyborohydride (82.5 g, 390 mmol) in portions over aperiod of ten minutes. Reaction mixture was stirred at room temperaturefor 16 h. Then saturated aqueous sodium bicarbonate solution was addedto the reaction and the resulting mixture was stirred for another 30minutes. The reaction mixture was then further basified with aqueoussodium carbonate to pH=˜10. Dichloromethane layer was separated and theaqueous layer extracted with dichloromethane (3×100 mL). Organic layerswere combined, washed with brine, dried over anhydrous sodium sulfate,and evaporated to give titled product as a colorless oil (yield: 72%).¹HNMR (300 MHz, CDCl₃): δ 0.92-0.98 (m, 6H), 1.28-1.41 (m, 5H),2.48-2.68 (m, 3H), 3.30-3.40 (m, 1H), 3.74 (s, 3H).

Examples 2-12 were prepared from2-chloro-7-methyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-oneusing corresponding R³—NH₂, according to procedures similar for thepreparation of Example 1 above. Examples 13 was prepared according toprocedures similar for the preparation of Example 1 above usingcorresponding starting materials and intermediates. More specifically,acetone was used in the step a of the synthesis.

Ex. # Chemical Name Analytical Data 1 2-(1H-indazol-5-ylamino)-7- ¹HNMR(300 MHz, CDCl₃): δ 0.96-1.0 (m, methyl-8-(3-methylbutyl)-5- 6H), 1.54(d, J = 6.9 Hz, 3H), 1.62-1.67 (m, phenyl-7,8-dihydropteridin- 3H),3.10-3.16 (m, 1H), 4.15-4.22 (m, 1H), 6(5H)-one 4.36 (q, J = 6.6 Hz,1H), 7.03 (s, 1H), 7.23- 7.54 (m, 8H), 7.98 (s, 1H). 8.08 (s, 1H) and10.03 (s, 1H). MS(ES⁺): m/z = 442.00 [MH⁺]. HPLC: t_(R) = 3.09 (ZQ3,Polar_5 min). 2 2-[(3,5-difluoro-4- ¹H NMR (CD₃OD, 400 MHz,) δ 1.00 (d,J = hydroxyphenyl)amino]-7- 5.81 Hz, 3 H), 1.03 (d, J = 6.06 Hz, 3 H),methyl-8-(3-methylbutyl)-5- 1.53 (d, J = 6.82 Hz, 3 H), 1.60-1.80 (m, 3phenyl-7,8-dihydropteridin- H), 3.23-3.30 (m, 1 H), 4.10-4.20 (m, 1 H),6(5H)-one 4.40 (q, J = 6.74 Hz, 1 H), 6.93 (s, 1 H), 7.18- 7.35 (m, 4H), 7.48-7.55 (m, 1 H), 7.56- 7.64 (m, 2 H). MS (ES⁺): m/z 453.93 (MH⁺).HPLC: t_(R) = 3.51 min (OpenLynx, polar_5 min, ZQ3). 37-methyl-8-(3-methylbutyl)-2- ¹HNMR (300 MHz, CDCl₃) δ 0.97-1.01 (m,[(2-oxo-2,3-dihydro-1H-indol-5- 6H), 1.50 (d, J = 6.6 Hz, 3H), 1.60-1.79(m, yl)amino]-5-phenyl-7,8- 3H), 3.06-3.13 (m, 1H), 3.51 (s, 2H), 4.10-dihydropteridin-6(5H)-one 4.17 (m, 1H), 4.31 (q, J = 6.6 Hz, 1H), 6.73(d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 7.23 (s, 1H), 7.26-7.30 (m, 2H),7.47-7.56 (m, 4H), 8.53 (s, 1H). MS (ES⁺): m/z 456.89 [MH⁺]. HPLC: t_(R)= 3.00 min (OpenLynx, polar_5 min, ZQ3). 4 diethyl (4-{[7-methyl-8-(3-¹H NMR (CD₃OD, 400 MHz): δ 1.03 (d, J = methylbutyl)-6-oxo-5-phenyl-6.32 Hz, 3 H), 1.06 (d, J = 6.32 Hz, 3 H), 5,6,7,8-tetrahydropteridin-2-1.28 (t, J = 6.95 Hz, 6 H), 1.54 (d, J = 6.82 Hz,yl]amino}benzyl)phosphonate 3 H), 1.63-1.82 (m, 3 H), 3.14-3.19 (m, 1H), 3.22 (s, 1 H), 3.25-3.31 (m, 1 H), 3.98- 4.10 (m, 4 H), 4.20 (ddd, J= 13.71, 9.28, 6.32 Hz, 1 H), 4.42 (q, J = 6.82 Hz, 1 H), 6.97 (s, 1 H),7.22 (dd, J = 8.59, 2.53 Hz, 2 H), 7.31 (d, J = 7.33 Hz, 2 H) 7.50-7.56(m, 1 H). MS(ES⁺): m/z 552.24 [MH⁺]. HPLC: t_(R) = 1.28 (TOF, Polar_3min). 5 N-methyl-2-(4-{[7-methyl-8-(3- ¹H NMR (CDCl₃, 300 MHz): δ 0.97(d, J = 6.3 methylbutyl)-6-oxo-5-phenyl- Hz, 3H), 1.03 (d, J = 6.3 Hz,3H), 1.51(d, J = 5,6,7,8-tetrahydropteridin-2- 6.6 Hz, 3H), 1.63-1.76(m, 3H), 2.74 (d, J = yl]amino}phenyl)acetamide 4.8 Hz, 3H), 3.07-3.16(m, 1H), 3.53 (s, 2H), 4.13-4.22 (m, 1H), 4.34 (q, J = 6.9 Hz, 1H),5.36(s, 1H), 6.84 (s, 1H), 7.08(s, 1H), 7.13 (s, 1H), 7.16 (s, 1H), 7.23(s, 1H), 7.43-7.48 (m, 1H), 7.51-7.57 (m, 4H). ME(ES⁺): m/z = 473.13[MH⁺]. HPLC: t_(R) = 2.58 (ZQ3, Polar_5 min). 6N,N-dimethyl-2-(4-{[7-methyl- ¹H NMR (CD₃OD, 300 MHz): δ 0.95 (d, J =8-(3-methylbutyl)-6-oxo-5- 6.3 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H), 1.50(d, phenyl-5,6,7,8- J = 6.6 Hz, 3H), 1.62-1.76 (m, 3H), 2.94 (s,tetrahydropteridin-2- 3H), 2.99(s, 3H), 3.05-3.17 (m, 1H), 3.69 (s,yl]amino}phenyl)acetamide 2H), 4.14-4.20 (m, 1H), 4.38 (q, J = 6.9 Hz,1H), 6.91(s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H),7.48-7.60 (m, 5H). MS(ES⁺): m/z = 487.16 (100) [MH⁺]. HPLC: t_(R) = 2.95(ZQ3, Polar_5 min). 7 N-methyl-1-(4-{[7-methyl-8-(3- ¹H NMR (CDCl₃, 300MHz): δ 0.95 (d, J = 6.3 methylbutyl)-6-oxo-5-phenyl- Hz, 3H), 1.02 (d,J = 6.3 Hz, 3H), 1.51(d, J = 5,6,7,8-tetrahydropteridin-2- 6.9 Hz, 3H),1.63-1.70(m, 3H), 2.68 (d, J = 5.4 yl]amino}phenyl)methanesulfonamideHz, 3H), 3.11-3.16 (m, 1H), 4.19 (s, 2H), 4.31-4.35 (m, 2H), 7.06(s,1H), 7.15(s, 1H), 7.23-7.28 (m, 3H), 7.44-7.59 (m, 5H). MS(ES⁺): m/z =509.01 [MH⁺]. HPLC: t_(R) = 3.12 (ZQ3, Polar_5 min). 8N,N-dimethyl-1-(4-{[7-methyl- ¹H NMR (CDCl₃, 300 MHz): δ 1.00 (t, J =6.9 8-(3-methylbutyl)-6-oxo-5- Hz, 6H), 1.51(d, J = 6.6 Hz, 3H), 1.63-phenyl-5,6,7,8- 1.74(m, 3H), 2.72 (s, 6H), 3.10-3.15 (m, 1H),tetrahydropteridin-2- 4.13-4.23 (m, 1H), 4.20 (s, 2H), 4.34 (q, J =yl]amino}phenyl)methanesulfonamide 6.9 Hz, 1H), 6.94 (s, 1H), 7.09(s,1H), 7.23- 7.30(m, 3H), 7.44-7.62(m, 5H). MS(ES⁺): m/z 523.14 [MH⁺].HPLC: t_(R) = 3.33 (ZQ3, Polar_5 min). 9 methyl 4-{[7-methyl-8-(3- ¹HNMR (CDCl₃, 400 MHz): δ 1.02 (d, J = methylbutyl)-6-oxo-5-phenyl- 6.57Hz, 3 H), 1.04 (d, J = 6.57 Hz, 3 H), 5,6,7,8-tetrahydropteridin-2- 1.53(d, J = 6.82 Hz, 3 H), 1.63-1.80 (m, 3 yl]amino}benzoate H), 3.09-3.22(m, 1 H), 3.89 (s, 3 H), 4.12- 4.24 (m, 1 H), 4.36 (q, J = 6.82 Hz, 1H), 7.08 (s, 1 H), 7.11 (s, 1 H), 7.24 (s, 1 H), 7.44-7.50 (m, 1 H),7.51-7.57 (m, 2 H), 7.61-7.67 (m, 2 H), 7.92-8.00 (m, 2 H). MS(ES⁺): m/z460.15 [MH⁺]. HPLC: t_(R) = 3.61 (ZQ3, Polar_5 min). 10 methyl3-{[7-methyl-8-(3- MS(ES⁺): m/z 460.21 [MH⁺]. HPLC: t_(R) = 1.46methylbutyl)-6-oxo-5-phenyl- (TOF, Polar_3 min).5,6,7,8-tetrahydropteridin-2- yl]amino}benzoate 11 2-[(trans-4- ¹H NMR(CD₃OD, 400 MHz): δ 1.03 (d, J = hydroxycyclohexyl)amino]-7- 6.50 Hz, 3H), 1.05 (d, J = 6.50 Hz, 3 H), methyl-8-(3-methylbutyl)-5- 1.27-1.44(m, 4 H) 1.51 (d, J = 6.82 Hz, 3 phenyl-7,8-dihydropteridin- H)1.61-1.76 (m, 3 H), 1.95-2.08 (m, 4 H), 6(5H)-one 3.24 (ddd, J = 13.83,9.03, 5.18 Hz, 1 H), 3.50-3.63 (m, 1 H), 3.64-3.75 (m, 1 H), 4.05-4.18(m, 1 H), 4.36 (q, J = 6.74 Hz, 1 H), 6.78 (s, 1 H), 7.28 (d, J = 7.33Hz, 2 H), 7.47-7.54 (m, 1 H), 7.54-7.63 (m, 2 H). MS(ES⁺): m/z 424.24[MH⁺]. HPLC: t_(R) = 0.99 (TOF, Polar_3 min). 12 2-[(cis-4- ¹H NMR(CD₃OD, 400 MHz): δ 1.02 (d, J = hydroxycyclohexyl)amino]-7- 6.80 Hz, 3H), 1.04 (d, J = 6.80 Hz, 3 H), methyl-8-(3-methylbutyl)-5- 1.51 (d, J =6.57 Hz, 3 H), 1.62-1.80 (m, 11 phenyl-7,8-dihydropteridin- H), 3.23(ddd, J = 13.89, 8.97, 5.43 Hz, 1 H), 6(5H)-one 3.74-3.89 (m, 2 H),4.07-4.18 (m, 1 H), 4.36 (q, J = 6.74 Hz, 1 H), 6.77-6.83 (m, 1 H),7.24-7.33 (m, 2 H), 7.48-7.55 (m, 1 H) 7.55-7.63 (m, 2 H). MS(ES⁺): m/z424.22 [MH⁺]. HPLC: t_(R) = 2.50 (ZQ3, Polar_5 min). 132-(1H-indazol-5-ylamino)-7- ¹H NMR (CDCl₃, 300 MHz): δ 1.38 (d, J =methyl-5-phenyl-8-(propan-2- 6.50 Hz, 3 H), 1.42 (d, J = 6.50 Hz, 3 H),yl)-7,8-dihydropteridin-6(5H)- 1.50 (d, J = 6.9 Hz, 3H), 2.17 (s, 1H),4.46 one (q, J = 6.6 Hz, 1H), 4.75-4.84 (m, 1H), 7.03 (s, 1H), 7.16 (s,1H), 7.23(s, 1H), 7.39-7.41 (m, 2H), 7.43-7.54 (m, 3H), 7.98 (s, 1H),8.11 (s, 1H), 10.18 (br. s, 1H). MS(ES⁺): m/z = 414.03 [MH⁺]. HPLC:t_(R) = 2.47 (ZQ3, Polar_5 min).

Examples 14: To a stirred solution of methyl4-{[7-methyl-8-(3-methylbutyl)-6-oxo-5-phenyl-5,6,7,8-tetrahydropteridin-2-yl]amino}benzoate(46 mg, 0.1 mmol) in dioxane (contains 4N HCl, 5.0 mL) was added 6Naqueous HCl (1.0 mL) at rt. The resulting solution was stirred at 70° C.for 3 h. Then the solvent was removed under reduced pressure to give aresidue, which was purified by recrystallization in acetonitrile to givetitled compound (example 14, yield: 56%).

Example 15 was prepared from Example 10 according to procedures similarfor the preparation of Example 14.

Ex. # Name Analytical data 14 4-{[7-methyl-8-(3- ¹H NMR (DMSO-d₆, 400MHz): δ 0.96 (d, J = 6.32 methylbutyl)-6-oxo-5- Hz, 3 H), 0.98 (d, J =6.32 Hz, 3 H), 1.53 (d, J = phenyl-5,6,7,8- 6.82 Hz, 3 H), 1.56-1.78 (m,3 H), 3.31-3.42 (m, tetrahydropteridin-2- 1 H), 3.44-3.53 (m, 1 H), 4.55(m, J = 6.80 Hz, 1 yl]amino}benzoic acid H), 6.87 (s, 1 H), 7.37 (d, J =7.07 Hz, 2 H), 7.50- 7.56 (m, 1 H), 7.57-7.64 (m, 2 H), 7.76 (d, J =8.84 Hz, 2 H), 7.82-7.90 (m, 2 H). MS(ES⁺): m/z 446.17 [MH⁺]. HPLC:t_(R) = 2.92 (ZQ3, Polar_5 min). 15 3-{[7-methyl-8-(3- ¹H NMR (DMSO-d₆,400 MHz): δ 0.87 (d, J = 6.50 methylbutyl)-6-oxo-5- Hz, 3 H), 0.88 (d, J= 6.50 Hz, 3 H), 1.47-1.70 phenyl-5,6,7,8- (m, 6 H), 3.30-3.41 (m, 1 H),4.01-4.07 (m, 1H), tetrahydropteridin-2- 4.51-4.60 (m, 1 H), 6.81 (s, 1H), 7.37 (d, J = yl]amino}benzoic acid 7.07 Hz, 2 H), 7.44 (t, J = 7.83Hz, 1 H), 7.51- 7.57 (m, 1 H), 7.57-7.68 (m, 3 H), 7.81 (d, J = 7.83 Hz,1 H), 8.23 (s, 1 H). MS(ES⁺): m/z 446.14 [MH⁺]. HPLC: t_(R) = 2.75 (ZQ3,Polar_5 min).

Example 16 was prepared according to procedures similar for thepreparation of Example 1 above using corresponding starting materialsand intermediates. More specifically, D-alanine methyl esterhydrochloride was used in the step a of the synthesis.

Example 17 was prepared according to procedures similar for thepreparation of Example 1 above using corresponding starting materialsand intermediates. More specifically, L-alanine methyl esterhydrochloride was used in the step a of the synthesis.

Ex. # Chemical Name Analytical data 16 (7R)-2-(1H-indazol-5-ylamino)-7-¹H NMR, Mass and HPLC methyl-8-(3-methylbutyl)-5-phenyl- are identicalto Example 1 7,8-dihydropteridin-6(5H)-one 17(7S)-2-(1H-indazol-5-ylamino)-7- ¹H NMR, Mass and HPLCmethyl-8-(3-methylbutyl)-5-phenyl- are identical to Example 17,8-dihydropteridin-6(5H)-one

Synthesis of Examples 18-59

Example 18(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one

Step e: Synthesis of Example 18

A mixture of(7R)-2-chloro-8-cyclohexyl-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one(114 mg, 0.32 mmol), 5-aminoindazole (53 mg, 0.40 mmol), trifluoroaceticacid (1.3 mmol) in trifluoroethanol (2.0 ml) was heated in a microwavereactor at 125° C. for 30 minutes. The reaction mixture was diluted withethyl acetate (50 ml) and washed with aqueous saturated sodiumbicarbonate, dried and evaporated. The residue was purified by columnchromatography on silica gel using 3% methanol in dichloromethane aseluent to give the titled compound (yield: 41%).

Step d: synthesis of(7R)-2-chloro-8-cyclohexyl-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one

To a solution of(7R)-2-chloro-8-cyclohexyl-7-methyl-7,8-dihydropteridin-6(5H)-one (280mg, 1.0 mmol) in 10 mL of dry dichloromethane was added triethylamine(1.39 mL, 10 mmol), cupric acetate (363 mg, 2.0 mmol), phenylboronicacid (244 mg, 2.0 mmol) and 4 Å molecular sieves (2.0 g). The reactionmixture was allowed to stir at room temperature with air balloon on. Thereaction mixture was then filtered over Celite, washed withdichloromethane and the organic layer was washed with aqueous sodiumbicarbonate, dried over anhydrous sodium sulfate and evaporated. Theresidue was purified by silica gel flash chromatography, usingdichloromethane-methanol mixture (v:v=99:1) as eluent, to give titledcompound (yield: 39%). ¹HNMR (300 MHz, CDCl₃): δ 1.20-1.22 (m, 1H),1.47-1.49 (m, 6H), 1.72-1.77 (m, 3H), 1.87-1.89 (m, 2H), 2.10-2.13 (m,1H), 4.44-4.49 (m, 2H), 7.17 (s, 1H), 7.20-7.24 (m, 2H), 7.48-7.56 (m,3H).

Step c: Synthesis of(7R)-2-chloro-8-cyclohexyl-7-methyl-7,8-dihydropteridin-6(5H)-one To asolution of methylN-(2-chloro-5-nitropyrimidin-4-yl)-N-cyclohexyl-D-alaninate (9.9 g, 29mmol) in 100 mL of ethanol was added iron powder (16.2 g, 290 mmol). Theresulting mixture was heated to reflux, then 2N HCl (10 mL) was added insmall proportions. The reaction mixture was heated at reflux until thecompletion of the reaction as monitored by TLC. The reaction was cooledto room temperature and filtered. The filtrate was evaporated to give aresidue which was triturated using isopropyl ether to give titledcompound (yield: 62%). ¹HNMR (300 MHz, DMSO-d₆): δ 1.11-1.20 (m, 1H),1.25-1.34 (m, 6H), 1.59-1.60 (m, 3H), 1.75-1.90 (m, 3H), 4.05 (t, J=11.7Hz, 1H), 4.25 (q, J=6.9 Hz, 1H), 7.60 (s, 1H), 10.23 (br s, 1H).

Step b: Synthesis of MethylN-(2-chloro-5-nitropyrimidin-4-yl)-N-cyclohexyl-D-alaninate

To a solution of 2,4-dichloro-5-nitropyrimidine (28.5 g, 146.9 mmol) inether (200 mL) was added methyl N-cyclohexyl-D-alaninate (17.0 g, 91.8mmol) at −10° C. To the resulting solution was then added aqueouspotassium carbonate (19.0 g in 100 mL water) drop wise while maintainingthe temperature below 0° C. Reaction mixture was then warmed to rt andstirred at rt for 16 h. The organic layer was separated and the aqueouslayer was extracted with ether (3×75 mL). Combined ether solution waswashed with brine, dried over anhydrous sodium sulfate and evaporated.The residue was purified by silica gel flash chromatography using ethylacetate-hexane mixture (v:v=5:95) as eluent to give titled compound(yield, 41%). ¹HNMR (300 MHz, CDCl₃): δ 1.06-1.29 (m, 3H), 1.43-1.53 (m,2H), 1.58 (s, 1H), 1.64 (d, J=6.9 Hz, 3H), 1.90-1.82 (m, 2H), 2.02-1.98(m, 1H), 2.17-2.14 (m, 1H), 3.09-3.01 (m, 1H), 3.73 (s, 3H), 4.13 (q,J=6.9 Hz, 1H), 8.59 (s, 1H).

Step a: Synthesis of methyl N-cyclohexyl-D-alaninate

To a suspension of D-Alanine methyl ester hydrochloride (16.0 g, 114.6mmol) in dry dichloromethane (150 mL) was added potassium acetate (11.2g, 114.6 mmol) and the reaction mixture stirred for ten minutes. Thereaction mixture was then cooled to 10° C., cyclohexanone (11.8 mL,114.6 mmol) was added, followed by sodium triacetoxyborohydride (30.3 g,143.2 mmol) in portions over a period of ten minutes. Reaction mixturewas stirred at room temperature for 16 h after which saturated sodiumbicarbonate solution (60 mL) was added and stirred for another 30minutes. The reaction mixture was further basified with aqueous sodiumcarbonate to pH=˜10. The organic layer was separated and the aqueouslayer extracted with dichloromethane (3×75 mL). The organic layers werecombined, washed with brine, dried over anhydrous sodium sulfate, andevaporated to give titled compound (yield: 80%). ¹HNMR (300 MHz, CDCl₃):δ 0.97-1.21 (m, 4H), 1.26 (d, J=6.9 Hz, 3H), 1.57-1.59 (m, 2H),1.75-1.67 (m, 3H), 1.89-1.84 (m, 1H), 2.36-2.29 (m, 1H), 3.48 (q, J=6.9Hz, 1H), 3.70 (s, 3H).

Examples 19-59 were prepared according to procedures similar for thepreparation of Example 18 above, using corresponding R¹—B(OH)₂ andR³—NH₂.

Examples 60 was prepared according to procedures similar for thepreparation of Example 18 above using corresponding starting materialsand intermediates. More specifically, DL-alanine methyl esterhydrochloride was used in the step a of the synthesis,5-amino-1,3-dihydro-2H-indol-2-one as corresponding R³—NH₂ was used inthe step e of the synthesis.

Examples 61 was prepared according to procedures similar for thepreparation of Example 18 above using corresponding starting materials.More specifically, DL-alanine methyl ester hydrochloride was used in thestep a of the synthesis.

Examples 62 was prepared according to procedures similar for thepreparation of Example 18 above using corresponding starting materials.More specifically, L-alanine methyl ester hydrochloride was used in thestep a of the synthesis.

Synthesis of Example 63: To a stirred solution of methyl4-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzoate(51 mg, 0.1 mmol) in dioxane (contains 4N HCl, 5.0 mL) was added 6Naqueous HCl (1.0 mL) at rt. The resulting solution was stirred at 70° C.for 3 h. Then the solvent was removed under reduced pressure to give aresidue, which was purified by recrystallization in acetonitrile to givetitled compound (Example 63, yield: 45%).

Ex. # Chemical Name Analytical data 18 (7R)-8-cyclohexyl-2-(1H- ¹H NMR(CDCl₃, 300 MHz): δ 1.23-1.26 (m, 1H), indazol-5-ylamino)-7- 1.45-1.50(m, 6H), 1.69-1.87 (m, 3H), 1.92-1.96 (m, methyl-5-phenyl-7,8- 2H),2.23-2.25 (m, 1H), 4.41-4.50 (m, 2H), 7.07 (s, dihydropteridin-6(5H)-1H), 7.15 (s, 1H), 7.22(s, 1H), 7.39-7.54 (m, 5H), one 7.99 (s, 1H),8.16 (s, 1H). MS(ES⁺): m/z = 453.90 [MH⁺]. HPLC: t_(R) = 2.55 (ZQ3,Polar_5 min). 19 4-[(7R)-8-cyclohexyl-2- ¹H NMR (CDCl₃, 300 MHz): δ1.24-1.27 (m, 1H), (1H-indazol-5-ylamino)- 1.46-1.53 (m, 6H), 1.66-1.80(m, 3H), 1.92-1.96 (m, 7-methyl-6-oxo-7,8- 2H), 2.23-2.28 (m, 1H),4.42-4.46 (m, 2H), 7.01 (s, dihydropteridin-5(6H)- 1H), 7.17 (s, 1H),7.37-7.45 (m, 4H), 7.81 (d, J = yl]benzonitrile 8.7 Hz, 2H), 8.00 (s,1H), 8.16 (s, 1H). MS(ES⁺): m/z = 479.10 [MH⁺]. HPLC: t_(R) = 2.59 (ZQ3,Polar_5 min). Optical rotation: [α]_(D) = +20.0 (C = 0.4 in CH₂Cl₂) 20(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃ and CD₃OD, 300 MHz): δ 1.12-1.13indazol-5-ylamino)-7- (m, 1H), 1.34-1.40 (m, 6H), 1.58-1.71 (m, 3H),1.82- methyl-5-(pyridin-4-yl)- 1.86 (m, 2H), 2.11-2.14 (m, 1H),4.32-4.38 (m, 2H), 7,8-dihydropteridin- 7.10 (s, 1H), 7.21 (d, J = 6.3Hz, 2H), 7.29-7.37 (m, 6(5H)-one 2H), 7.84 (s, 1H), 8.03 (s, 1H), 8.63(d, J = 5.1 Hz, 2H). MS(ES⁺): m/z = 455.18 [MH⁺]. HPLC: t_(R) = 2.31(ZQ3, Polar_5 min). 21 (7R)-5-(4-chlorophenyl)- ¹H NMR (CDCl₃, 300 MHz):δ 1.24-1.26 (m, 1H), 8-cyclohexyl-2-(1H- 1.45-1.53 (m, 6H), 1.72-1.81(m,3H), 1.92-1.96 (m, indazol-5-ylamino)-7- 2H), 2.24-2.26 (m, 1H),4.43-4.48 (m, 2H), 6.99 (s, methyl-7,8- 1H), 7.16-7.20 (m, 3H),7.40-7.50 (m, 4H), 7.99 (s, dihydropteridin-6(5H)- 1H), 8.16 (s, 1H).MS(ES⁺): m/z = 488.09, 490.03 one [MH⁺]. HPLC: t_(R) = 2.76 (ZQ3,Polar_5 min). Optical rotation: [α]_(D) = −12.5 (C = 0.4 in CH₂Cl₂) 22(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ: 1.19-2.22 (m, 2H),indazol-5-ylamino)-7- 1.46-1.53 (m, 6H), 1.68-1.96 (m, 4H), 2.24 (s,1H), methyl-5-(4- 2.41 (s, 3H), 4.45 (q, J = 6.9 Hz, 2H), 6.94 (s, 1H),methylphenyl)-7,8- 7.10-7.17 (m, 3H), 7.30-7.40 (m, 3H), 7.99 (s, 1H),dihydropteridin-6(5H)- 8.00 (s, 1H), 8.18 (s, 1H), 10.08 (s, 1H).MS(ES⁺): one m/z = 468.15 [MH⁺]. HPLC: t_(R) = 2.97 (ZQ3, Polar_5 min).23 (7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃ and CD₃OD, 300 MHz) δ1.07-1.28 indazol-5-ylamino)-7- (m, 1H), 1.28-1.46 (m, 6H), 1.54-1.78(m, 3H), 1.80- methyl-5-(pyridin-3-yl)- 1.89 (m, 2H), 2.09-2.20 (m, 1H),4.32-4.39 (m, 2H), 7,8-dihydropteridin- 6.97 (s, 1H), 7.32 (t, J = 8.1Hz, 2H), 7.41-7.46 (m, 6(5H)-one 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.81 (s,1H), 8.01 (s, 1H), 8.37 (s, 1H), 8.54 (d, J = 4.8 Hz, 1H). MS(ES⁺): m/z= 455.13 [MH⁺]. HPLC: t_(R) = 2.15 (ZQ3, Polar_5 min). Optical rotation:[α]_(D) = −56.0 (C = 0.5 in 1N HCl). 24 (7R)-8-cyclohexyl-5-(4- ¹H NMR(CDCl₃, 300 MHz): δ 1.23-1.25 (m, 1H), fluorophenyl)-2-(1H- 1.42-1.53(m, 6H), 1.71-1.82 (m, 3H), 1.92-1.96 (m, indazol-5-ylamino)-7- 2H),2.24 (s, 1H), 4.42-4.49 (m, 2H), 7.00 (s, 1H), methyl-7,8- 7.15 (s, 1H),7.20-7.22 (m, 4H), 7.36-7.43 (m, 2H), dihydropteridin-6(5H)- 8.00 (s,1H), 8.16 (s, 1H), 10.14 (br. s, 1H). one MS(ES⁺): m/z = 472.12 [MH⁺].HPLC: t_(R) = 2.54 (Polar_5 min, ZQ3). Optical rotation: [α]_(D) = −47.5(C = 0.4 in CH₂Cl₂) 25 (7R)-8-cyclohexyl-5-(3- ¹H NMR (CDCl₃, 300MHz): δ 1.23-1.25 (m, 1H), fluorophenyl)-2-(1H- 1.42-1.53 (m, 6H),1.72-1.81 (m, 3H), 1.92-1.96 (m, indazol-5-ylamino)-7- 2H), 2.23-2.35(m, 1H), 4.42-4.49 (m, 2H), 6.98- methyl-7,8- 7.06 (m, 3H), 7.13-7.18(m, 2H), 7.37-7.41 (m, 2H), dihydropteridin-6(5H)- 7.44-7.53 (m, 1H),8.00 (s, 1H), 8.16 (s, 1H), 10.11 one (br. s, 1H). MS(ES⁺): m/z = 472.12[MH⁺]. HPLC: _(tR) = 2.58 (Polar_5 min, ZQ3). Optical rotation: [α]_(D)= −48.0 (C = 0.5 in CH₂Cl₂) 26 (7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃,300 MHz) δ 1.26-1.40 (m, 1H), indazol-5-ylamino)-5-(4- 1.50-1.57 (m,4H), 1.72-2.03 (m, 7H), 2.30-3.36 (m, methoxyphenyl)-7- 1H), 3.92 (s,3H), 4.50-4.57(m, 2H), 7.09 (d, J = 9 methyl-7,8- Hz, 2H), 7.21-7.26 (m,2H), 7.33 (s, 1H), 7.46 (s, dihydropteridin-6(5H)- 2H), 8.07 (s, 1H),8.25 (s, 1H). MS(ES⁺): m/z = one 484.15 [MH⁺]. HPLC: t_(R) = 2.55(Polar_5 min, ZQ3). Optical rotation: [α]_(D) = −17.0 (C = 0.7 inCH2Cl2). 27 4-[(7R)-8-cyclohexyl-2- ¹H NMR (CDCl₃ and CD₃OD, 300 MHz) δ1.15-1.30 (1H-indazol-5-ylamino)- (m, 1H), 1.44-1.50 (m, 6H), 1.61-1.85(m, 3H), 1.87- 7-methyl-6-oxo-7,8- 1.93 m, 2H), 2.22-2.35 (m, 1H), 3.01(s, 3 H), 3.10 dihydropteridin-5(6H)-yl]- (s, 3H), 4.38-4.50 (m, 2H),7.11 (s, 1H), 7.25-7.27 N,N-dimethylbenzamide (m, 1H), 7.28 (s, 1H),7.31-7.40 (m, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.92 (s, 1H), 8.14 (s, 1H).MS(ES⁺): m/z = 525.15 [MH⁺]. HPLC: t_(R) = 2.15 (ZQ3, Polar_5 min). 28(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz): δ 1.22-1.24 (m, 1H),indazol-5-ylamino)-5-(3- 1.47-1.53 (m, 6H), 1.68-1.83 (m, 3H), 1.94-1.96(m, methoxyphenyl)-7- 2H), 2.23-2.24 (m, 1H), 3.81 (s, 3H), 4.42-4.49(m, methyl-7,8- 2H), 6.74 (s, 1H), 6.82 (d, J = 7.2 Hz, 1H), 6.96-7.00dihydropteridin-6(5H)- (m, 2H), 7.18 (s, 1H), 7.36-7.44 (m, 3H), 7.99(s,1H), one 8.17 (s, 1H), 10.10 (br. s, 1H). MS(ES⁺): m/z = 484.28 [MH⁺].HPLC: t_(R) = 2.47 (ZQ3, Polar_5 min). Optical rotation: [α]_(D) = −20.0(C = 0.4 in CH₂Cl₂) 29 3-[(7R)-8-cyclohexyl-2- ¹H NMR (CDCl₃, 300 MHz):δ 1.24-1.25 (m, 1H), (1H-indazol-5-ylamino)- 1.47-1.53 (m, 6H),1.68-1.81 (m, 3H), 1.92-1.96 (m, 7-methyl-6-oxo-7,8- 2H), 2.23-2.35 (m,1H), 4.44-4.47 (m, 2H), 6.97 (s, dihydropteridin-5(6H)- 1H), 7.15 (s,1H), 7.37-7.45 (m, 2H), 7.52 (d, J = yl]benzonitrile 8.7 Hz, 1H),7.59-7.66 (m, 2H), 7.72-7.75 (m, 1H), 8.00 (s, 1H), 8.15 (s, 1H), 10.07(br. s, 1H). MS(ES⁺): m/z = 479.24 [MH⁺]. HPLC: t_(R) = 2.48 (ZQ3,Polar_5 min). Optical rotation: [α]_(D) = −50.0 (C = 0.4 in CH₂Cl₂) 30(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz): δ 1.19-1.23 (m, 1H),indazol-5-ylamino)-7- 1.47-1.53 (m, 6H), 1.68-1.83 (m, 3H), 1.92-1.96(m, methyl-5-(3- 2H), 2.24-2.25 (m, 1H), 2.38 (s, 3H), 4.42-4.49 (m,methylphenyl)-7,8- 2H), 6.95 (s, 1H), 7.03-7.04 (m, 2H), 7.15 (s, 1H),dihydropteridin-6(5H)- 7.23 (s, 1H), 7.36-7.42 (m, 3H), 7.99 (s, 1H),8.17 one (s, 1H), 10.09 (br. s, 1H). MS(ES⁺): m/z = 468.21 [MH⁺]. HPLC:t_(R) = 2.75 (ZQ3, Polar_5 min). Optical rotation: [α]_(D) = −30.0 (C =0.4 in CH₂Cl₂) 31 (7R)-5-(3-chlorophenyl)- ¹H NMR (CDCl₃, 300 MHz): δ1.23-1.25 (m, 1H), 8-cyclohexyl-2-(1H- 1.46-1.53 (m, 6H), 1.67-1.81 (m,3H), 1.96-1.98 (m, indazol-5-ylamino)-7- 2H), 2.21-2.23 (m, 1H),4.41-4.48 (m, 2H), 6.93 (s, methyl-7,8- 1H), 7.14-7.18 (m, 2H),7.37-7.48 (m, 4H), 8.00 (s, dihydropteridin-6(5H)- 1H), 8.16 (s, 1H),10.02 (br. s, 1H). MS(ES⁺): m/z = one 488.15, 490.12 [MH⁺]. HPLC: t_(R)= 2.75 (ZQ3, Polar_5 min). Optical rotation: [α]_(D) = −27.5 (C = 0.4 inCH₂Cl₂) 32 3-[(7R)-8-cyclohexyl-2- ¹H NMR (CDCl₃, 300 MHz): δ 1.21-1.23(m, 1H), (1H-indazol-5-ylamino)- 1.45-1.53 (m, 6H), 1.67-1.82 (m, 3H),1.95-1.97 (m, 7-methyl-6-oxo-7,8- 2H), 2.23-2.24 (m, 1H), 3.02 (s, 3H),3.10 (s, 3H), dihydropteridin-5(6H)-yl]- 4.43-4.47 (m, 2H), 7.00 (s,1H), 7.22 (s, 1H), 7.28- N,N-dimethylbenzamide 7.34 (m, 2H), 7.38-7.43(m, 2H), 7.49-7.58 (m, 2H), 8.00(s, 1H), 8.17 (s, 1H), 10.13 (br. s,1H). Optical rotation: MS(ES⁺): m/z = 525.21 [MH⁺]. HPLC: t_(R) = 2.22(ZQ3, Polar_5 min). Optical rotation: [α]_(D) = −23.33 (C = 0.6 inCH₂Cl₂) 33 (7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃ and CD₃OD, 300 MHz) δ1.10-1.30 indazol-5-ylamino)-7- (m, 1H), 1.40-1.49 (m, 6H), 1.60-1.85(3H), 1.89- methyl-5-[4- 1.92 (m, 2H), 2.19-2.30 (m, 1H), 4.39-4.45 (m,2H), (trifluoromethoxy)phenyl]- 7.06 (s, 1H), 7.23 (s, 1H), 7.32-7.41(m, 5H), 7.92 7,8-dihydropteridin- (s, 1H), 8.11 (s, 1H); MS(ES⁺): m/z =538.13 [MH⁺]. 6(5H)-one HPLC: t_(R) = 3.04 (ZQ3, Polar_5 min). Opticalrotation: [α]_(D) = −52.0 (C = 0.25 in CH₂Cl₂) 34(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ 1.18-1.24 (m, 1H),indazol-5-ylamino)-7- 1.46-1.67 (m, 5H), 1.68-1.96 (m, 6H), 2.20-2.40(m, methyl-5-[3- 1H), 4.40-4.49 (m, 2H), 7.14-7.27 (m, 4H), 7.29-(trifluoromethoxy)phenyl]- 7.36 (m, 2H), 7.39 (s, 1H), 7.55 (t, J = 7.8Hz, 1H), 7,8-dihydropteridin- 8.00 (s, 1H), 8.16 (s, 1H), 10.4 (br. s,1H). MS(ES⁺) 6(5H)-one m/z = 538.16 [MH⁺]. HPLC: t_(R) = 3.01 (ZQ3,Polar_5 min). Optical rotation: [α]_(D) = −66.0 (C = 0.5 in CH₂Cl₂). 35(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ 1.15-1.30 (m, 1H),indazol-5-ylamino)-7- 1.46-1.57 (m, 6H), 1.60-2.00 (m, 5H), 2.20-2.40(m, methyl-5-[4- 1H), 4.42-4.51 (m, 2H), 7.08 (s, 1H), 7.19 (s, 1H),(trifluoromethyl)phenyl]- 7.38-7.41 (m, 4H), 7.78 (d, J = 8.1 Hz, 2H),8.03 (s, 7,8-dihydropteridin- 1H), 8.17 (s, 1H), 10.20 (br. s, 1H);MS(ES⁺): m/z = 6(5H)-one 522.18 [MH⁺]. HPLC: t_(R) = 2.98 (ZQ3, Polar_5min). Optical rotation: [α]_(D) = −44.0 (C = 0.25 in CH₂Cl₂). 36(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ 1.19-1.30 (m, 1H),indazol-5-ylamino)-7- 1.48-1.53 (m, 6H), 1.68-1.96 (m, 5H), 2.20-2.30(m, methyl-5-[3- 1H), 4.41-4.50 (m, 2H), 7.07 (s, 1H), 7.13 (s, 1H),(trifluoromethyl)phenyl]- 7.36-7.47 (m, 3H), 7.53 (s, 1H), 7.63-7.72 (m,2H), 7,8-dihydropteridin- 8.00 (s, 1H), 8.16 (s, 1H), 10.20 (br s, 1H);6(5H)-one MS(ES⁺): m/z = 522.18 [MH⁺]. HPLC: t_(R) = 2.94 (ZQ3, Polar_5min). Optical rotation: [α]_(D) = −58.0 (C = 0.5 in CH₂Cl₂) 374-[(7R)-8-cyclohexyl-2- ¹H NMR (DMSO-d₆, 300 MHz) δ 1.20-1.30 (m, 1H),(1H-indazol-5-ylamino)- 1.36-1.45 (m, 4H), 1.59-1.84 (m, 7H), 2.02-2.18(m, 7-methyl-6-oxo-7,8- 1H), 2.47-2.50 (m, 3H), 4.38-4.46 (m, 2H), 7.08(s, dihydropteridin-5(6H)-yl]- 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.51 (d, J= 9 Hz, 1H), N- 7.55-7.61 (m, 3H), 7.90 (m 3H), 8.22 (s, 1H), 9.18methylbenzenesulfonamide (s, 1H). MS(ES⁺): m/z = 547.18 [MH⁺]. HPLC:t_(R) = 2.40 (ZQ3, Polar_5 min). 38 (7R)-8-cyclohexyl-2-(1H- ¹H NMR(CDCl₃, 300 MHz): δ 1.22-1.24 (m, 1H), indazol-5-ylamino)-7- 1.42-1.54(m, 6H), 1.70-1.97 (m, 5H), 2.23-2.25 (m, methyl-5-(3,4,5- 1H), 3.84 (s,6H), 3.88 (s, 3H), 4.44-4.49 (m, 2H), trimethoxyphenyl)-7,8- 6.42 (s,2H), 7.08 (s, 1H), 7.20 (s, 1H), 7.37-7.43 dihydropteridin-6(5H)- (m,2H), 8.00 (s, 1H), 8.18 (s, 1H), 10.07 (br. s, 1H). one MS(ES⁺): m/z =544.24 [MH⁺]. HPLC: t_(R) = 2.41 (ZQ3, Polar_5 min). Optical rotation:[α]_(D) = −11.66 (C = 0.6 in CH₂Cl₂) 39 (7R)-5-(1,3-benzodioxol- ¹H NMR(CDCl₃, 300 MHz): δ 1.21-1.22 (m, 1H), 5-yl)-8-cyclohexyl-2-(1H-1.44-1.49 (m, 6H), 1.68-1.81 (m, 3H), 1.92-1.95 (m,indazol-5-ylamino)-7- 2H), 2.23-2.25 (m, 1H), 4.41-4.47 (m, 2H), 6.04(s, methyl-7,8- 2H), 6.68-6.71 (m, 2H), 6.90-6.94 (m, 2H), 7.22 (s,dihydropteridin-6(5H)- 1H), 7.36-7.43 (m, 2H), 7.99 (s, 1H), 8.17 (s,1H), one 10.07 (br. s, 1H). MS(ES⁺): m/z = 498.13 [MH⁺]. HPLC: t_(R) =2.39 (Polar_5 min, ZQ3). Optical rotation: [α]_(D) = −27.5 (C = 0.4 inCH₃OH) 40 (7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz): δ 1.10-1.19(m, 1H), indazol-5-ylamino)-7- 1.42-1.46 (m, 6H), 1.70-1.78 (m, 3H),1.87-1.89 (m, methyl-5-[4- 2H), 2.20-2.22 (m, 1H), 3.09 (s, 3H),4.40-4.43 (m, (methylsulfonyl)phenyl]- 2H), 7.07-7.11 (m, 1H), 7.38 (d,J = 7.8 Hz, 2H), 7,8-dihydropteridin- 7.46 (d, J = 8.1 Hz, 2H),7.90-7.92 (m, 1H), 8.05- 6(5H)-one 8.09 (m, 3H). MS(ES⁺): m/z = 532.14[MH⁺]. HPLC: t_(R) = 2.33 (Polar_5 min, ZQ3). 41 (7R)-8-cyclohexyl-5-[4-¹H NMR (CDCl₃ and CD₃OD, 300 MHz): δ 1.20-1.22 (dimethylamino)phenyl]-(m, 1H), 1.33-1.42(m, 6H), 1.61-1.74(m, 3H), 1.83- 2-(1H-indazol-5-1.87(m, 2H), 2.14-2.16 (m, 1H), 2.91(s, 6H), 4.32-ylamino)-7-methyl-7,8- 4.38 (m, 2H), 6.71 (d, J = 9.0 Hz, 2H), 6.95(d, J= dihydropteridin-6(5H)- 8.1 Hz, 2H), 7.04(s, 1H), 7.29-7.37 (m, 2H),7.85 (s, one 1H), 8.06 (s, 1H). MS(ES⁺): m/z = 497.19 [MH⁺]. HPLC: t_(R)= 2.61 (Polar_5 min, ZQ3). 42 3-[(7R)-8-cyclohexyl-2- ¹H NMR (DMSO-d₆,300 MHz) δ 1.15-1.26 (m, 1H), (1H-indazol-5-ylamino)- 1.32-1.51 (m, 4H),1.59-1.87 (m, 7H), 2.07-2.10 (m, 7-methyl-6-oxo-7,8- 1H), 2.44 (d, J =4.5 Hz, 3H), 4.37-4.46 (m, 2H), 7.03 dihydropteridin-5(6H)-yl]- (s, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 9 Hz, N- 1H), 7.58-7.64 (m,2H), 7.70 (s, 1H), 7.78 (t, J = 7.8 methylbenzenesulfonamide Hz, 1H),7.85-7.88 (m, 2H), 8.21 (s, 1H), 9.17 (s, 1H). MS(ES⁺): m/z = 547.13[MH⁺]. HPLC: t_(R) = 2.55 (Polar_5 min, ZQ3). 43(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃ and CD₃OD, 300 MHz): δ 1.20-1.22indazol-5-ylamino)-7- (m, 1H), 1.43-1.48(m, 6H), 1.64-1.78(m, 3H), 1.88-methyl-5-[3- 1.91(m, 2H), 2.18-2.19 (m, 1H), 3.08(s, 3H), 4.42 (q,(methylsulfonyl)phenyl]- J = 6.9 Hz, 2H), 7.05(s, 1H), 7.32-7.40 (m,2H), 7,8-dihydropteridin- 7.51(d, J = 7.5 Hz, 1H), 7.70(t, J = 7.8 Hz,1H), 6(5H)-one 7.82(s, 1H), 7.91(s, 1 H), 7.97(d, J = 8.1 Hz, 1H),8.10(s, 1H). MS(ES⁺): m/z = 532.14 [MH⁺]. HPLC: t_(R) = 2.33 (Polar_5min, ZQ3). 44 (7R)-8-cyclohexyl-5-[3- ¹H NMR (CDCl₃, 300 MHz): δ1.23-1.28 (m, 1H), (dimethylamino)phenyl]- 1.47-1.53(m, 6H),1.69-1.84(m, 3H), 1.93-1.95(m, 2-(1H-indazol-5- 2H), 2.25-2.27(m, 1H),2.94(s, 6H), 4.43-4.49 (m, ylamino)-7-methyl-7,8- 2H), 6.46 (s, 1H),6.53-6.55 (m, 1H), 6.74-7.77 (m, dihydropteridin-6(5H)- 1H), 7.14(s,1H), 7.22(s, 1H), 7.31-7.38 (m, 3H), one 7.99(s, 1H), 8.18(s, 1H), 10.39(br. s, 1H). MS(ES⁺): m/z = 497.23 [MH⁺]. HPLC: t_(R) = 2.56 (Polar_5min, ZQ3). Optical rotation: [α]_(D) = −26.66 (C = 0.6 in CH₂Cl₂). 45(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ 1.20-1.33 (m, 1H),indazol-5-ylamino)-7- 1.43-1.55 (m, 6H), 1.71-1.97 (m, 5H), 2.24-2.29(m, methyl-5-(naphthalen-2- 1H), 4.47-4.52 (m, 2H), 7.19 (s, 1H),7.27-7.30 (m, yl)-7,8-dihydropteridin- 2H), 7.37 (s, 2H), 7.53-7.58 (m,2H), 7.77 (s, 1H), 6(5H)-one 7.83-7.92 (m, 2H), 7.98 (d, J = 8.7 Hz,2H), 8.17 (s, 1H)., 10.20 (br. s, 1H); MS(ES⁺): m/z = 504.23 [MH⁺].HPLC: t_(R) = 2.86 (Polar_5 min, ZQ3). Optical rotation: [α]_(D) = −36.0(C = 0.25 in CH₂Cl₂). 46 3-[(7R)-8-cyclohexyl-2- ¹H NMR (CDCl₃ andCD₃OD, 300 MHz) δ 1.15-1.22 (1H-indazol-5-ylamino)- (m, 1H), 1.39-1.44(m, 6H) 1.60-1.95 (m, 5H), 2.17- 7-methyl-6-oxo-7,8- 2.24 (m, 1H), 2.89(s, 3H), 4.39-4.41 (m, 2H), 7.02 dihydropteridin-5(6H)-yl]- (s, 1H),7.27-7.35 (m, 3H), 7.51 (d, J = 8.1 Hz, 1H), N-methylbenzamide 7.55-7.57(m, 1H), 7.81(d, J = 3.3 Hz, 1H), 7.85 (s, 1H), 8.08 (s, 1H); MS(ES⁺):m/z = 511.23 [MH⁺]. HPLC: t_(R) = 2.15 (Polar_5 min, ZQ3). 47N-{4-[(7R)-8-cyclohexyl- ¹H NMR (CDCl₃ and CD₃OD, 300 MHz): δ 0.97-0.992-(1H-indazol-5- (m, 1H), 1.21-1.30(m, 6H), 1.47-1.57(m, 3H), 1.66-ylamino)-7-methyl-6-oxo- 1.70(m, 2H), 1.97-1.99(m, 1H), 2.78 (s, 3H),4.16- 7,8-dihydropteridin-5(6H)- 4.22 (m, 2H), 6.82(s, 1H), 6.94(d, J =8.1 Hz, 2H), yl]phenyl}methanesulfonamide 7.13-7.22 (m, 4H), 7.66 (s,1H), 7.86(s, 1H). MS(ES⁺): m/z = 547.07 [MH⁺]. HPLC: t_(R) = 2.25 (ZQ3,Polar_5 min). 48 (7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ:1.18-1.27 (m, 1 H), indazol-5-ylamino)-5-(6- 1.46-1.53 (m, 5 H),1.68-1.83 (m, 4 H), 1.87-1.96 methoxypyridin-3-yl)-7- (m, 2 H),2.20-2.60 (m, 1 H), 3.98 (s, 3 H), 4.43-4.49 methyl-7,8- (m, 2 H), 6.88(s, 1 H), 7.04 (s, 1 H), 7.20 (s, 1 H), dihydropteridin-6(5H)- 7.36-7.45(m, 3 H), 8.01 (s, 1 H), 8.05 (d, J = 2.1 Hz, one 1 H), 8.16 (s, 1 H),10.10 (br. s, 1 H); MS(ES⁺): m/z = 485.11 [MH⁺]. HPLC: t_(R) = 2.39(ZQ3, Polar_5 min). 49 (7R)-8-cyclohexyl-5-(3,4- ¹H NMR (CDCl₃, 300 MHz)δ: 1.18-1.23 (m, 1 H), difluorophenyl)-2-(1H- 1.45-1.52 (m, 5 H),1.68-1.85 (m, 4 H), 1.90-2.01 indazol-5-ylamino)-7- (m, 2 H), 2.20-2.38(m, 1 H), 4.41-4.48 (m, 2 H), methyl-7,8- 6.99-7.05 (m, 1 H), 7.06-7.15(m, 2 H), 7.18 (s, 1 H), dihydropteridin-6(5H)- 7.31 (d, J = 9.3 Hz, 1H), 7.35-7.43 (m, 2 H), 8.00 one (s, 1 H), 8.16 (s, 1 H), 10.20 (br. s,1 H); MS(ES⁺): m/z = 490.07 [MH⁺]. HPLC: t_(R) = 2.69 (ZQ3, Polar_5min). Optical rotation: [α]_(D) = −65 (C = 0.4 in CH2Cl2). 50(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃ and CD₃OD, 300 MHz) δ: 1.14-1.25indazol-5-ylamino)-7- (m, 1H), 1.40-1.50 (m, 6H), 1.60-1.79 (m, 3H),1.81- methyl-5-(quinolin-3-yl)- 1.92 (m, 2H), 2.19-2.22 (m, 1H),4.37-4.49 (m, 2H), 7,8-dihydropteridin- 7.10 (s, 1H), 7.32-7.40 (m, 2H),7.60 (t, J = 7.2 6(5H)-one Hz, 1H), 7.75-7.84 (m, 2H), 7.88 (s, 1H),8.11 (d, J = 9.3 Hz, 3H), 8.65 (d, J = 2.1 Hz, 1H); MS(ES⁺): m/z =505.19 [MH⁺]. HPLC: t_(R) = 2.51 (ZQ3, Polar_5 min). 513-[(7R)-8-cyclohexyl-7- ¹H NMR (CDCl₃, 300 MHz): δ 1.22-1.24 (m, 1 H),methyl-6-oxo-2-[(2-oxo- 1.39-1.50 (m, 6H), 1.65-1.84 (m, 3H), 1.91-1.95(m, 2,3-dihydro-1H-indol-5- 2H), 2.18-2.28 (m, 1H), 3.54 (s, 2 H),4.39-4.48 (m, yl)amino]-7,8- 2H), 6.77 (d, J = 8.7 Hz, 1H), 7.11 (s,2H), 7.27- dihydropteridin-5(6H)- 7.31(m, 1H), 7.49-7.52(m, 1H), 7.58(s, 1H), 7.61- yl]benzonitrile 7.66 (m, 2H), 7.71-7.74 (m, 1H), 8.81(br. s, 1H); MS(ES⁺): m/z = 494.16 [MH⁺]. HPLC: t_(R) = 2.42 (ZQ3,Polar_5 min). Optical rotation: [α]_(D) = −48.88 (C = 0.9 in CH₂Cl₂) 52methyl 4-[(7R)-8- ¹H NMR (CDCl₃, 300 MHz) δ: 1.20-1.26 (m, 1H),cyclohexyl-2-(1H- 1.47-1.53 (m, 6H), 1.67-1.86 (m, 3H), 1.80-1.96 (m,indazol-5-ylamino)-7- 2H), 2.42-2.58 (m, 1H), 3.95 (s, 3H), 4.42-4.49(m, methyl-6-oxo-7,8- 2H), 6.99 (s, 1H), 7.17 (s, 1H), 7.32-7.44 (m,4H), dihydropteridin-5(6H)- 8.00 (s, 1H), 8.17-8.20 (m, 3H), 10.10 (brs, yl]benzoate 1H); MS(ES⁺): m/z = 512.19 [MH⁺]. HPLC: t_(R) = 2.62(ZQ3, Polar_5 min). 53 5-[(7R)-8-cyclohexyl-2- ¹H NMR (CDCl₃, 300 MHz)δ: 1.18-1.24 (m, 1H), (1H-indazol-5-ylamino)- 1.46-1.52 (m, 6H),1.70-1.86 (m, 3H), 1.80-2.01 (m, 7-methyl-6-oxo-7,8- 2H), 2.42-2.57 (m,1H), 2.61 (s, 3H), 4.39-4.48 (m, dihydropteridin-5(6H)-yl]- 2H), 7.04(s, 1H), 7.14 (s, 1H), 7.36-7.39 (m, 2H), 2-methylbenzonitrile 7.41 (s,1H), 7.44-7.48 (m, 1H), 7.52 (d, J = 2.4 Hz, 1H), 8.00 (s, 1H), 8.16 (s,1H), 10.19 (br. s, 1H). MS(ES⁺): m/z = 493.19 [MH⁺]. HPLC: t_(R) = 2.62(ZQ3, Polar_5 min). Optical rotation: [α]_(D) = −77.5 (C = 0.4 inCH₂Cl₂). 54 (7R)-8-cyclohexyl-5-(4- ¹H NMR (CDCl₃, 300 MHz) δ: 1.19-1.27(m, 1H), fluoro-3-methoxyphenyl)- 1.47-1.64 (m, 6H), 1.73-1.83 (m, 3H),1.96-2.00 (m, 2-(1H-indazol-5- 2H), 2.21-2.35 (m, 1H), 3.87 (s, 3H),4.42-4.49 (m, ylamino)-7-methyl-7,8- 2H), 6.78-6.70 (m, 2H), 7.01 (s,1H), 7.11-7.25 (m, dihydropteridin-6(5H)- 2H), 7.36-7.44 (m, 2H), 8.01(s, 1H), 8.17 (s, 1H), one 10.11 (br. s, 1H). MS(ES⁺): m/z = 502.18[MH⁺]. HPLC: t_(R) = 2.53 (ZQ3, Polar_5 min). 55 (7R)-8-cyclohexyl-5-(3-¹H NMR (CDCl₃, 300 MHz) δ: 1.16-1.25 (m, 1H), fluoro-4-methoxyphenyl)-1.45-1.52 (m, 6H), 1.72-1.83 (m, 3H), 1.91-1.98 (m, 2-(1H-indazol-5-2H), 2.23-2.29 (m, 1H), 3.94 (s, 3H), 4.40-4.61 (m,ylamino)-7-methyl-7,8- 2H), 6.97-7.01 (m, 3H), 7.07 (t, J = 8.4 Hz, 1H),7.19 dihydropteridin-6(5H)- (s, 1H), 7.36-7.44 (m, 2H), 7.99 (s, 1H),8.16 (s, one 1H), 10.10 (br. s, 1H). MS(ES⁺): m/z = 502.16 [MH⁺]. HPLC:t_(R) = 2.49 (ZQ3, Polar_5 min). 56 3-[(7R)-8-cyclohexyl-2- ¹H NMR(CDCl₃, 300 MHz) δ: 1.20-1.26 (m, 1 H), [(6-fluoro-1H-indazol-5-1.47-1.62 (m, 6H), 1.73-1.83 (m, 3H), 1.97-1.99 (m,yl)amino]-7-methyl-6- 2H), 2.25-2.27 (m, 1H), 4.45-4.49 (m, 2H), 7.11(s, oxo-7,8-dihydropteridin- 1H), 7.18-7.22 (m, 2H), 7.51-7.54 (m, 1H),7.60- 5(6H)-yl]benzonitrile 7.62 (m, 1H), 7.65-7.67 (m, 1H), 7.73-7.75(m, 1H), 7.99 (s, 1H), 8.69 (d, J = 7.8 Hz, 1H), 10.21 (br. s, 1H).MS(ES⁺): m/z = 497.12 [MH⁺]. HPLC: t_(R) = 2.65 (ZQ3, Polar_5 min).Optical rotation: [α]_(D) = −55.55 (C = 0.9 in CH₂Cl₂). 57(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ: 1.18-1.25 (m, 1 H),indazol-5-ylamino)-7- 1.44-1.52 (m, 3H), 1.60-1.70 (m, 3H), 1.72-1.81(m, methyl-5-(thiophen-3-yl)- 3H), 1.91-1.98 (m, 2H), 2.20-2.36 (m, 1H),4.41- 7,8-dihydropteridin- 4.47 (m, 2H), 6.96 (dd, J = 5.4, 1.2 Hz, 1H),7.00 (s, 6(5H)-one 1H), 7.31-7.33 (m, 2H), 7.40-7.41 (m, 2H), 7.44- 7.47(m, 1H), 8.00 (s, 1H), 8.17 (m, 1H); MS(ES⁺): m/z = 460.16 [MH⁺]. HPLC:t_(R) = 2.35 (ZQ3, Polar_5 min). Optical rotation: [α]_(D) = −51.0 (C =1.0 in CH₂Cl₂). 58 (7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ:1.22-1.27 (m, 1 H), indazol-5-ylamino)-7- 1.39-1.66 (m, 6H), 1.69-1.84(m, 3H), 1.97-2.27 (m, methyl-5-(1-methyl-1H- 2H), 2.22-2.28 (m, 1H),3.95 (s, 3H), 4.40-4.45 (m, pyrazol-4-yl)-7,8- 2H), 7.15 (s, 1H),7.39-7.44 (m, 2H), 7.49-7.52 (m, dihydropteridin-6(5H)- 3H), 8.00 (s,1H), 8.18 (s, 1H). MS(ES⁺): m/z = one 458.14 [MH⁺]. HPLC: t_(R) = 2.09(ZQ3, Polar_5 in). Optical rotation: [α]_(D) = −24.0 (C = 0.5 inCH₂Cl₂). 59 3-[(7R)-8-cyclohexyl-7- ¹H NMR (CDCl₃, 300 MHz) δ: 0.87-0.89(m, 1 H), methyl-2-[(7-methyl-1H- 1.42-1.48 (m, 6H), 1.74-1.80 (m, 3H),1.92-2.04 (m, indazol-5-yl)amino]-6- 2H), 2.22-2.26 (m, 1H), 2.53 (s,3H), 4.42-4.49 (m, oxo-7,8-dihydropteridin- 2H), 6.97-7.05(m, 1H), 7.14(s, 2H), 7.50-7.53 (m, 5(6H)-yl]benzonitrile 1H), 7.59-7.65 (m, 2H),7.71-7.74 (m, 1H), 8.00 (s, 2H), 10.41 (br. s, 1H). MS(ES⁺): m/z =493.16 [MH⁺]. HPLC: t_(R) = 2.56 (ZQ3, Polar_5 min). Optical rotation:[α]_(D) = −38.88 (C = 0.6 in CH₂Cl₂) 60 8-cyclohexyl-7-methyl-2- ¹H NMR(300 MHz, DMSO-d₆): δ: 1.21-1.22 (m, [(2-oxo-2,3-dihydro-1H- 1H),1.34-1.38 (m, 6H), 1.61-1.82 (m, 5H), 2.04- indol-5-yl)amino]-5- 2.07(m, 1H), 3.41 (s, 2H), 4.20-4.32 (m, 2H), 6.66 phenyl-7,8- (d, J = 8.7Hz, 1H), 6.92 (s, 1H), 7.28 (d, J = 7.5 Hz, dihydropteridin-6(5H)- 2H),7.46-7.54 (m, 4H), 7.60 (s, 1H), 9.02 (s, 1H), one 10.17 (br s, 1H).MS(ES⁺): m/z = 469.10 [MH⁺]. HPLC: t_(R) = 2.45 (ZQ3, Polar_5 min). 618-cyclohexyl-2-(1H- ¹H NMR, Mass and HPLC data: identical toindazol-5-ylamino)-7- Example 18 methyl-5-phenyl-7,8-dihydropteridin-6(5H)- one 62 (7S)-8-cyclohexyl-2-(1H- ¹H NMR, Mass andHPLC data: identical to indazol-5-ylamino)-7- Example 18methyl-5-phenyl-7,8- dihydropteridin-6(5H)- one 634-[(7R)-8-cyclohexyl-2- ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.21-1.26 (m, 2H),(1 H-indazol-5-ylamino)- 1.50-1.52 (m, 4H), 1.65-1.81 (m, 4H), 1.86-1.89(m, 7-methyl-6-oxo-7,8- 1H), 1.92-2.03 (m, 2H), 4.10-4.19 (m, 1H), 4.54-dihydropteridin-5(6H)- 4.63 (m, 1H), 6.89 (s, 1H), 7.38 (d, J = 9 Hz,1H), yl]benzoic acid 7.49-7.57 (m, 3H), 7.94(s, 1H), 8.03 (s, 1H), 8.11-8.14 (m, 2H), 10.09 (br s, 1H). MS(ES⁺): m/z = 498.14 [MH⁺]. HPLC: t_(R)= 2.27 (ZQ3, Polar_5 min).

Example 64 was prepared according to procedures similar for thepreparation of Example 18 above using corresponding starting materialsand intermediates. More specifically, DL-alanine methyl esterhydrochloride and cyclopentanone was used in the step a of thesynthesis.

Example 65 was prepared according to procedures similar for thepreparation of Example 18 above using corresponding starting materialsand intermediates. More specifically, DL-alanine methyl esterhydrochloride and cyclopentanone was used in the step a of thesynthesis. 5-amino-1,3-dihydro-2H-indol-2-one as corresponding R³—NH₂was used in the step e of the synthesis.

Example 66 was prepared according to procedures similar for thepreparation of Example 18 above using corresponding starting materialsand intermediates. More specifically, cyclopentanone was used in thestep a of the synthesis.

Example 67 was prepared according to procedures similar for thepreparation of Example 18 above using corresponding starting materialsand intermediates. More specifically, L-alanine methyl esterhydrochloride and cyclopentanone was used in the step a of thesynthesis.

Example 68 was prepared according to procedures similar for thepreparation of Example 18 above using corresponding starting materialsand intermediates. More specifically, cyclopentanone was used in thestep a of the synthesis. 5-amino-1,3-dihydro-2H-indol-2-one ascorresponding R³—NH₂ was used in the step e of the synthesis.

Example 69 was prepared according to procedures similar for thepreparation of Example 18 above using corresponding starting materialsand intermediates. More specifically, cyclopentanone was used in thestep a of the synthesis. (3-Cyanophenyl)boronic acid as correspondingR¹—B(OH)₂ was used in the step d of the synthesis.

Ex. # Chemical Name Analytical data 64 8-cyclopentyl-2-(1H-indazol-¹HNMR (CDCl₃, 300 MHz): δ 1.47 (d, J = 6.6 Hz, 5-ylamino)-7-methyl-5-3H), 1.68-1.81 (m, 6H), 2.04-2.13 (m, 2H), phenyl-7,8-dihydropteridin-4.43(q, J = 6.9 Hz, 1H), 4.46-4.59 (m, 1H), 7.01 6(5H)-one (s, 1H), 7.16(s, 1H), 7.24 (s, 1H), 7.38 (s, 2H), 7.41-7.46(m, 1H), 7.49-7.54(m, 2H),7.98 (s, 1H), 8.11 (s, 1H), 10.18 (br. s, 1H). MS(ES⁺): m/z = 439.98[MH⁺]. HPLC: t_(R) = 2.33 (ZQ3, Polar_5 min). 658-cyclopentyl-7-methyl-2- ¹H NMR (CDCl₃, 300 MHz): δ 1.46 (d, J = 6.9Hz, [(2-oxo-2,3-dihydro-1H- 3H), 1.68-1.80 (m, 6H), 2.04-2.11 (m, 2H),indol-5-yl)amino]-5-phenyl- 3.51(s, 2H), 4.41(q, J = 6.6 Hz, 1H),4.51-4.55 7,8-dihydropteridin-6(5H)- (m, 1H), 6.74-6.76 (m, 2H), 7.12(s,1H), 7.22 (s, one 1H), 7.41-7.49(m, 3H), 7.60 (s, 1H), 7.70 (s, 1H).MS(ES⁺): m/z = 454.90 [MH⁺]. HPLC: t_(R) = 2.21 (ZQ3, Polar_5 min). 66(7R)-8-cyclopentyl-2-(1H- ¹HNMR, Mass, HPLC are identical to exampleindazol-5-ylamino)-7- 64. methyl-5-phenyl-7,8- dihydropteridin-6(5H)-one67 (7S)-8-cyclopentyl-2-(1H- ¹HNMR, Mass, HPLC are identical to exampleindazol-5-ylamino)-7- 64. methyl-5-phenyl-7,8- dihydropteridin-6(5H)-one68 (7R)-8-cyclopentyl-7- ¹HNMR, Mass, HPLC are identical to examplemethyl-2-[(2-oxo-2,3- 65. dihydro-1H-indol-5- yl)amino]-5-phenyl-7,8-dihydropteridin-6(5H)-one 69 3-[(7R)-8-cyclopentyl-2-(1H- ¹H NMR (CDCl₃,300 MHz) δ: 1.46-1.48 (m, 4H), indazol-5-ylamino)-7- 1.61-1.62 (m, 2H),1.68-1.81 (m, 4H), , 2.06- methyl-6-oxo-7,8- 2.15 (m, 1H), 4.42 (q, , J= 6.9 Hz, 1H), 4.46- dihydropteridin-5(6H)- 4.57 (m, 1H), 6.91-6.94 (m,1H), 7.15 (s, 1H), yl]benzonitrile 7.36-7.44 (m, 2H), 7.52-7.66 (m, 3H),7.72-7.56 (s, 1H), 7.99 (s, 1H), 8.09 (s, 1H). MS(ES⁺): m/z = 465.13[MH⁺]. HPLC: t_(R) = 2.36 (ZQ3, Polar_5 min).

Example 70 was prepared from methyl 2-methylalaninate hydrochlorideusing procedures shown below:

Step a: Methyl 2-methyl-N-(3-methylbutyl)alaninate

A suspension of methyl 2-methylalaninate hydrochloride (6.9 g, 45 mmol)in dry dichloromethane (180 mL) was treated with potassium acetate (4.4g, 45 mmol) and the reaction mixture stirred for ten minutes. Thereaction mixture was then cooled to 10° C. and treated with3-methylbutanal (4.8 g, 56 mmol). This was followed by the addition ofsodium triacetoxyborohydride (11.91 g, 56 mmol) in portions over aperiod of ten minutes. Reaction mixture was stirred at room temperaturefor 16 h. Then saturated aqueous sodium bicarbonate solution was addedto the reaction and resulting mixture was stirred for another 30minutes. The reaction mixture was further basified with aqueous sodiumcarbonate to pH=˜10. Dichloromethane layer was separated and the aqueouslayer extracted with dichloromethane (3×50 mL). Organic layers werecombined, washed with brine, dried over anhydrous sodium sulfate, andevaporated to give titled product as colorless oil which was used assuch for the next step. ¹HNMR (300 MHz, CDCl₃): δ 0.95 (s, 3H), 0.96 (s,3H), 1.25-1.35 (m, 7H), 1.55-1.65 (m, 1H), 1.80 (s, 1H), 2.40-2.48 (m,2H), 3.63 (s, 3H).

Step b: MethylN-(2-chloro-5-nitropyrimidin-4-yl)-2-methyl-N-(3-methylbutyl)alaninate

To a stirred suspension of 2,4-dichloro-5-nitropyrimidine (7.5 g, 38.5mmol), anhydrous potassium carbonate (10.0 g) in dry acetone (150 mL)was added a solution of methyl 2-methyl-N-(3-methylbutyl)alaninate (5.6g, 30.0 mmol) in dry acetone (9 mL) at 0° C. The reaction was thenallowed to warm up to room temperature and stirred at rt for 16 h. Thereaction mixture was filtered and evaporated. The residue was purifiedby flash chromatography on silica gel (eluent: ethyl acetate-hexanemixture (v:v=5:95)) to give titled product (yield: 15%). ¹HNMR (300 MHz,CDCl₃): δ 0.85 (s, 3H), 0.88 (s, 3H), 1.30-1.36 (m, 2H), 1.60-1.65 (m,7H), 3.37-3.42 (m, 2H), 3.72 (s, 3H) and 8.56 (s, 1H).

Step c:2-Chloro-7,7-dimethyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one

To a stirred solution of methylN-(2-chloro-5-nitropyrimidin-4-yl)-2-methyl-N-(3-methylbutyl)alaninate(2.0 g, 5.8 mmol) in ethanol (125 mL) was added iron powder (3.2 g, 58mmol), the resulting mixture was heated to reflux. 1N aqueoushydrochloric acid was added to the reaction mixture (added in smallportions, 5.0 ml total), The reaction mixture was heated at reflux untilthe completion of the reaction as monitored by TLC. The reaction wascooled to room temperature and filtered. The filtrate was evaporated togive a residue which was triturated using isopropyl ether to give titledcompound (yield: 65%). ¹HNMR (300 MHz, CDCl₃): δ 0.97 (s, 3H), 1.0 (s,3H), 1.37-1.56 (m, 7H), 1.65-1.80 (m, 2H), 3.52-3.58 (m, 2H), 7.62 (s,1H), 9.13 (br s, 1H).

Step d:2-Chloro-7,7-dimethyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one

To a stirred solution of2-chloro-7,7-dimethyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one(707 mg, 2.5 mmol) in dichloromethane (50 mL) was added triethylamine(25.0 mmol), cupric acetate (908 mg, 5.0 mmol) and phenylboronic acid(610 mg, 5.0 mmol) followed by 4 Å molecular sieves (2.0 g). Thereaction mixture was stirred for 48 h at room temperature with an airballoon. Then the reaction mixture was filtered over celite. Thefiltrate was washed with aqueous saturated sodium bicarbonate (2×30 mL),dried over anhydrous sodium sulfate and evaporated. The residue waspurified by column chromatography on silica gel (Eluent: 2% methanol indichloromethane) to give titled product (yield; 46%). ¹HNMR (300 MHz,CDCl₃): δ 1.0 (s, 3H), 1.02 (s, 3H), 1.61-1.65 (m, 9H), 3.64 (q, J=5.1Hz, 2H), 7.06 (s, 1H), 7.18-7.21 (m, 2H) and 7.48-7.57 (m, 3H).

Step e:2-(1H-indazol-5-ylamino)-7,7-dimethyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-oneExample 70

A mixture of2-chloro-7,7-dimethyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one(89 mg, 0.25 mmol), 5-aminoindazole (41 mg, 0.31 mmol), trifluoroaceticacid (1.0 mmol) in trifluoroethanol (1.5 mL) was heated in a microwavereactor at 125° C. for 35 minutes. The reaction mixture was diluted withethyl acetate (30 ml) and washed with aqueous saturated sodiumbicarbonate, dried over anhydrous sodium sulfate and evaporated. Theresidue was purified by column chromatography on silica gel using 2%methanol in dichloromethane as eluent to give titled compound (yield:30%). ¹HNMR (300 MHz, CDCl₃): δ 0.98 (s, 3H), 1.0 (s, 3H), 1.64-1.85 (m,9H), 3.64-3.69 (m, 2H), 7.05 (s, 1H), 7.18-7.24 (m, 2H), 7.40-7.55 (m,5H), 7.98 (s, 1H), 8.08 (s, 1H), 10.04 (br. s, 1H). MS(ES⁺): m/z=456.10[MH⁺]. HPLC: t_(R)=2.76 (ZQ3, Polar_5 min).

Ex. # Chemical Name Analytical data 71 3-[(7R)-8-(cyclobutylmethyl)-2-¹H NMR (CDCl₃, 300 MHz): δ 1.54 (d, J = 6.9 (1H-indazol-5-ylamino)-7-Hz, 3H), 1.83-2.08 (m, 4H), 2.17-2.30 (m, 2H), methyl-6-oxo-7,8-2.82-2.92 (m, 1H), 3.23 (q, J = 7.5 Hz, 1H), dihydropteridin-5(6H)-4.27-4.40 (m, 2H), 7.17 (s, 1H), 7.24 (s, 1H), yl]benzonitrile 7.42-7.49(m, 2H), 7.59-7.63 (m, 1H), 7.68-7.71 (m, 2H), 7.79-7.83 (m, 1H), 8.07(s, 1H), 8.20 (s, 1H), 10.53 (br s 1H). MS(ES⁺): m/z = 465.13 [MH⁺].HPLC: t_(R) = 2.25 (ZQ3, Polar_5 min) 72 (7R)-8-(cyclohexylmethyl)-2-¹HNMR (300 MHz, CDCl₃): δ 1.02-1.06 (m, 3H), (1H-indazol-5-ylamino)-7-1.20-1.24 (m, 3H), 1.47 (d, J = 6.6 Hz, 3H), 1.76- methyl-5-phenyl-7,8-1.89 (m, 5H), 2.73 (q, J = 7.8 Hz, 1H), 4.18 (q,dihydropteridin-6(5H)-one J = 6.6 Hz, 1H), 4.28 (q, J = 6.9 Hz, 1H),6.86 (s, 1H), 7.14 (s, 1H), 7.28 (s, 1H), 7.34-7.56 (m, 5H), 7.98 (s,1H), 8.14 (s, 1H) and 10.1 (br s, 1H). MS(ES⁺): m/z = 468.28 [MH⁺].HPLC: t_(R) = 2.70 (ZQ3, Polar_5 min). 73 (7R)-8-[2- ¹HNMR (300 MHz,CDCl₃ + CD₃OD): δ 1.08-1.09 (dimethylamino)ethyl]-2-(1H- (m, 1H), 1.47(d, J = 6.9 Hz, 3H), 2.24 (s, 6H), indazol-5-ylamino)-7-methyl-5- 2.61(t, J = 7.2 Hz, 2H), 4.14-4.18, (m, 1H), 4.30phenyl-7,8-dihydropteridin- (q, J = 6.9 Hz, 1H), 6.98 (s, 1H), 7.19 (d,J = 6.0 Hz, 6(5H)-one 2H), 7.35-7.49 (m, 5H), 7.87 (s, 1H) 7.97 (s, 1H).MS(ES⁺): m/z = 443.22 [MH⁺]. HPLC: t_(R) = 0.75 (TOF, Polar3 min). 74(7R)-2-(1H-indazol-5-ylamino)- ¹HNMR (300 MHz, CDCl₃ + CD₃OD): δ1.29-1.34 7-methyl-5-phenyl-8- (m, 2H), 1.31 (d, J = 6.6 Hz, 3H),1.41-1.70 (m, (tetrahydro-2H-pyran-4- 2H), 1.90-2.10 (m, 1H), 2.70 (q, J= 7.5 Hz, 1H), ylmethyl)-7,8-dihydropteridin- 3.71-3.89 (m, 3H),4.17-4.19 (m, 3H), 6.90 (s, 6(5H)-one 1H), 7.16 (q, J = 8.4 Hz, 2H),7.30-7.49 (m, 5H), 7.82 (s, 1H), 7.95 (s, 1H). MS(ES⁺): m/z = 470.18(100) [MH⁺]. HPLC: t_(R) = 2.15 (ZQ3, Polar_5 min). 75(7R)-8-(cyclopentylmethyl)-2- ¹HNMR (300 MHz, CDCl₃): δ 1.23-1.40 (m,3H), (1H-indazol-5-ylamino)-7- 1.48 (d, J = 6.9 Hz, 3H), 1.56-1.69 (m,4H), 1.80- methyl-5-phenyl-7,8- 1.86 (m, 1H), 2.44 (q, J = 7.5 Hz, 1H),2.85-2.95 dihydropteridin-6(5H)-one (M, 1H), 4.22-4.36 (m, 2H), 7.02 (s,1H), 7.11 (s, 1H), 7.24-7.38 (m, 2H), 7.38-7.39 (m, 1H), 7.41-7.56 (m,3H), 7.98 (s, 1H), 8.13-8.14 (m, 1H), 10.20-10.30 (br s, 1H). ME(ES)+:m/z = 454.14 (100) [MH⁺]. HPLC: t_(R) = 2.45 (ZQ3, Polar_5 min). 76(7R)-8-benzyl-2-(1H-indazol-5- ¹HNMR (300 MHz, CDCl₃ + CD₃OD): δ 1.42(d, ylamino)-7-methyl-5-phenyl- J = 6.9 Hz, 3H), 4.22-4.44 (m, 1H), 4.33(d, J = 15.6 7,8-dihydropteridin-6(5H)-one Hz, 1H), 5.34 (d, J = 15.3Hz, 1H), 7.04 (s, 1H), 7.20-7.23 (m, 2H), 7.26-7.34(m, 6H), 7.42-7.52(m, 4H), 7.78 (s, 1H) and 7.91-7.92 (m, 1H). MS: m/z = 462.2 [M + H⁺].77 (7R)-8-(3-hydroxypropyl)-2- ¹HNMR (300 MHz, CDCl₃ + CD₃OD): δ 1.25(s, (1H-indazol-5-ylamino)-7- 1H), 1.52 (d, J = 6.6 Hz, 3H), 1.86-1.88(m, 2H), methyl-5-phenyl-7,8- 3.37-3.44 (m 2H), 4.08 (q, J = 6.3 Hz,1H), 4.30 dihydropteridin-6(5H)-one (q, J = 6.3 Hz 1H), 7.10 (s, 1H),7.22-7.30 (m, 4H), 7.33-7.53 (m, 3H) and 7.93 (s, 2H). MS: m/z = 430.2[M + H⁺]. 78 (7R)-2-(1H-indazol-5-ylamino)- ¹HNMR (300 MHz, CDCl₃) δ1.48 (d, J = 6.9 Hz, 7-methyl-5-phenyl-8-(piperidin- 3H), 1.98-2.12 (m,4H), 2.58-2.75 (m, 2H), 2.78- 4-ylmethyl)-7,8- 2.85 (m, 2H), 3.20-3.29(m, 4H), 4.18-4.29 (m, dihydropteridin-6(5H)-one 2H), 7.06 (s, 1H), 7.25(d, J = 7.5 Hz, 2H), 7.33- 7.58 (m, 5H) and 7.95 (d, J = 11.4 Hz, 2H).MS(ES⁺): m/z 469.23 [MH⁺]. HPLC: t_(R) = 2.29 (vvPolar_5 min, ZQ3). 79(7R)-2-(1H-indazol-5-ylamino)- ¹H NMR (CDCl₃, 300 MHz) δ: 1.02 (d, J =4.8 Hz, 7-methyl-8-(2-methylpropyl)-5- 3H), 1.04 (d, J = 4.8 Hz, 3H),1.47 (d, J = 6.9 Hz, phenyl-7,8-dihydropteridin- 3H), 2.17-2.23 (m, 1H),2.69 (q, J = 8.1 Hz, 1H), 6(5H)-one 4.16 (q, J = 6.9 Hz, 1H), 4.30-4.32(m, 1H), 7.13 (s, 1H), 7.28-7.35 (m, 2H), 7.36 (d, J = 1.5 Hz, 2H),7.42-7.56 (m, 3H), 7.99 (s, 1H) and 8.12 (t, J = 1.2 Hz, 1H). MS(ES⁺):m/z = 428.15 (100) [MH⁺]. HPLC: t_(R) = 2.39 (ZQ3, Polar_5 min). [α]_(D)= +43.1 (C = 0.53 in CH₂Cl₂) 80 3-[(7R)-2-(1H-indazol-5- ¹H NMR (CDCl₃,300 MHz): δ 1.90 (d, J = 6.0 ylamino)-7-methyl-6-oxo-8- Hz, 1H),1.48-1.57 (m, 6H), 2.01-2.02 (m, 1H), , (tetrahydro-2H-pyran-4- 2.84 (q,J = 7.8 Hz, 1H), 3.45 (t, J = 10.2 Hz, ylmethyl)-7,8-dihydropteridin-2H), 4.06-4.11 (m, 2H), 4.27-4.38 (m, 2H), 6.98- 5(6H)-yl]benzonitrile7.0 (m, 1H), 7.20 (s, 1H), 7.44-7.52 (m, 2H), 7.60-7.63 (m, 1H),7.70-7.84 (m, 3H), 8.05 (s, 1H) and 8.14 (s, 1H). MS(ES⁺): m/z = 495.11[MH⁺]. HPLC: t_(R) = 1.97 (ZQ3, Polar_5 min). 813-[(7R)-8-(cyclopentylmethyl)- ¹H NMR (CDCl₃, 300 MHz): δ 1.13 (d, J =6.0 2-(1H-indazol-5-ylamino)-7- Hz, 2H), 1.25-1.34 (m, 4H), 1.48 (d, J =6.9 Hz, methyl-6-oxo-7,8- 3H), 1.80-1.84 (m, 2H), 2.39-2.45 (m, 1H),2.87 dihydropteridin-5(6H)- (q, J = 6.9 Hz, 1H), 4.25 (q, J = 7.5 Hz,1H), yl]benzonitrile 4.36 (d, J = 6.9 Hz, 1H), 7.10 (s, 2H), 7.38- 7.41(m, 2H), 7.56-7.68 (m, 3H), 7.73-7.76 (m, 1H), 7.99 (s, 1H), 8.12 (s,1H). MS(ES⁺): m/z = 479.50 [MH⁺] 82 3-[(7R)-2-(1H-indazol-5- ¹H NMR(CDCl₃, 300 MHz) δ 1.48 (d, J = 6.6 Hz, ylamino)-7-methyl-6-oxo-8- 3H),1.69-1.76 (m, 1H), 2.04-2.15 (m, 1H), 2.81-(tetrahydrofuran-3-ylmethyl)- 2.83 (m, 1H), 2.91-3.01 (m, 1H), 3.66-3.84(m, 7,8-dihydropteridin-5(6H)- 3H), 3.86-3.96 (m, 1H), 4.20-4.34 (m,2H), 7.14 yl]benzonitrile (s, 1H), 7.35-7.42 (m, 2H), 7.53-7.56 (m, 1H),7.62-7.67 (m, 2H), 7.73-7.76 (m, 1H), 8.00-8.10 (m, 2H). MS(ES⁺): m/z =481.13 (100), [MH⁺]. HPLC: t_(R) = 2.78 (ZQ3, Polar_5 min). 833-[(7R)-8-[(3,3- ¹H NMR (CDCl₃, 300 MHz) δ 1.48 (d, J = 6.6 Hz,difluorocyclobutyl)methyl]-2- 3H), 2.37-2.43 (m, 2H), 2.68-2.77 (m, 3H),3.17 (1H-indazol-5-ylamino)-7- (q, J = 6.6 Hz, 1H), 4.27-4.38 (m, 2H),7.07 (s, methyl-6-oxo-7,8- 1H), 7.15 (s, 1H), 7.37-7.45 (m, 2H),7.53--7.56 dihydropteridin-5(6H)- (m, 1H), 7.62-7.68 (m, 2H), 7.75 (d, J= 7.5 Hz, yl]benzonitrile 1H), 8.02 (d, J = 7.5 Hz, 2H). MS(ES⁺): m/z =501.16 [MH⁺]. HPLC: t_(R) = 2.28 (ZQ3, Polar_5 min). 843-[(6aR)-2-[(7-fluoro-1H- ¹H NMR (DMSO-d6, 300 MHz) δ 2.04 (s, 3H),indazol-5-yl)amino]-6-oxo- 2.30 (s, 1H), 3.66-3.75 (m, 2H), 4.41 (m,1H), 6a,7,8,9-tetrahydropyrrolo[2,1- 6.93 (s, 1H), 7.58 (d, J = 13.5 Hz,1H), 7.73-7.76 h]pteridin-5(6H)-yl]benzonitrile (m, 2H), 7.94-8.04 (m,4H), 9.28 (s, 1H), 13.34 (s, 1H). MS(ES⁺): m/z = 441.40 [MH⁺]. 85(7R)-5-(3,4-dimethoxyphenyl)- ¹H NMR (CDCl₃, 300 MHz) δ 1.06 (t, J = 6.3Hz, 2-[(7-fluoro-1H-indazol-5- 6H), 1.60 (d, J = 6.9 Hz, 3H), 1.68-1.84(m, 3H), yl)amino]-7-methyl-8-(3- 3.18-3.22 (m, 1H), 3.94 (s, 3H), 4.0(s, 3H), 4.18- methylbutyl)-7,8- 4.30 (m, 1H), 4.42 (q, J = 6.9 Hz, 1H),6.77 (s, dihydropteridin-6(5H)-one 1H), 6.80-6.90 (m, 1H), 7.06 (d, J =7.7 Hz, 1H), 7.19 (s, 1H), 7.48 (dd,, J = 10.8 and 1.5 Hz, 1H), 7.78 (d,J = 1.5 Hz, 1H) and 8.07 (d, J = 1.5 Hz, 1H). MS(ES⁺): m/z = 520.85[MH⁺]. HPLC: t_(R) = 2.43 (ZQ3, Polar_5 min). 863-[(7R)-2-[(7-fluoro-1H- ¹H NMR (CDCl₃, 300 MHz) δ 0.99 (t, J = 6.3 Hz,indazol-5-yl)amino]-7-methyl- 6H), 1.52 (d, J = 6.6 Hz, 3H), 1.62-1.72(m, 3H), 8-(3-methylbutyl)-6-oxo-7,8- 3.10-3.16 (m, 1H), 4.12-4.16 (m,1H), 4.35-4.37 dihydropteridin-5(6H)- (m, 1H), 7.10 (s, 1H), 7.36-7.40(m, 2H), 7.52- yl]benzonitrile 7.56 (m, 1H), 7.61-7.67 (m, 2H),7.72-7.76 (m, 2H) and 8.01 (d, J = 3.3 Hz, 1H). MS(ES⁺): m/z = 485.92[MH⁺]. HPLC: t_(R) = 2.45 (ZQ3, Polar_5 min). 87(7R)-2-[(7-fluoro-1H-indazol-5- ¹H NMR (CDCl₃ + CD₃OD, 300 MHz) δ: 0.90(t, J = yl)amino]-7-methyl-8-(3- 3.3 Hz, 6H), 1.45 (d, J = 6.6 Hz,3H),1.55-1.66 methylbutyl)-5-(pyridin-3-yl)- (m, 3H), 3.05-3.12 (m, 1H),4.04-4.14 (m, 1H), 7,8-dihydropteridin-6(5H)-one 4.25-4.31 (m, 1H), 6.95(s, 1H), 7.28-7.32 (m, 1H), 7.45-7.50 (m, 1H), 7.61-7.63 (m, 2H), 7.87(d, J = 3.0 Hz, 1H), 8.44 (s, 1H), and 8.60 (d, J 3.6 Hz, 1H). MS(ES⁺):m/z = 461.90 [MH⁺]. HPLC: t_(R) = 2.17 (ZQ3, Polar_5 min). 88(7R)-5-(3,4-dimethoxyphenyl)- ¹H NMR (400 MHz, CD₃OD): δ 0.88-1.08 (m,2-[(4-fluoro-2-oxo-2,3-dihydro- 5H), 0.91-1.07 (m, 6H), 1.27 (br. s.,2H), 1.43- 1,3-benzoxazol-6-yl)amino]-7- 1.57 (m, 3H), 1.67 (br. s.,3H), 3.78-3.95 (m, 6H), methyl-8-(3-methylbutyl)-7,8- 4.13 (br. s., 1H),4.37 (br. s., 1H), 6.83 (br. s., dihydropteridin-6(5H)-one 2H),6.96-7.14 (m, 2H), 7.30 (d, J = 11.37 Hz, 1H), 7.49 (br. s., 1H).MS(ES⁺): m/z = 537.67 [MH⁺]. HPLC: t_(R) = 0.91 min (analytical_2 min,UPLC). 89 3-[(7R)-2-[(3,5-difluoro-4- ¹H NMR (400 MHz, CD₃OD): δ7.84-7.90 (m, hydroxyphenyl)amino]-7- 1H), 7.79 (s, 1H), 7.75 (t, J =8.0 Hz, 1H), 7.62- methyl-8-(3-methylbutyl)-6- 7.67 (m, 1H), 7.17-7.29(m, 2H), 6.96 (s, 1H), oxo-7,8-dihydropteridin-5(6H)- 4.41 (q, J = 6.8Hz, 1H), 4.13 (ddd, J = 6.2, 9.4, yl]benzonitrile 13.7 Hz, 1H),3.23-3.28 (m, 1H), 1.59-1.79 (m, 3H), 1.52 (d, J = 6.8 Hz, 3H), 1.00 (t,J = 5.9 Hz, 6H). MS (ES⁺): m/z = 479.71 [MH⁺]. UPLC: t_(R) = 1.00 min(TOF: polar_2 min). 90 3-[(7R)-2-[(4-fluoro-2-oxo-2,3- ¹H NMR (400 MHz,CDCl₃): δ 0.96-1.04 (m, 6H), dihydro-1,3-benzoxazol-6- 1.56 (d, J = 6.82Hz, 3H), 1.61-1.79 (m, 3H), yl)amino]-7-methyl-8-(3- 3.13-3.25 (m, 1H),4.07-4.24 (m, 1H), 4.27-4.43 methylbutyl)-6-oxo-7,8- (m, 1H), 7.23 (d, J= 11.12 Hz, 1H), 7.50 (s, 1H), dihydropteridin-5(6H)- 7.55 (d, J = 8.08Hz, 1H), 7.61 (s, 1H), 7.70 (t, J = yl]benzonitrile 7.96 Hz, 1H),7.75-7.83 (m, 1H), 9.05 (br. s., 1H). MS(ES⁺): m/z = 502.20[MH⁺]. HPLC:t_(R) = 0.97 min (analytical_2 min, UPLC). 91 5-[(7R)-2-[(7-fluoro-1H-¹H NMR (CDCl₃, 300 MHz) δ: 0.98 (t, J = 6.3 Hz,indazol-5-yl)amino]-7-methyl- 6H), 1.51 (d, J = 6.9 Hz, 3H), 1.62-1.71(m, 3H), 8-(3-methylbutyl)-6-oxo-7,8- 3.12-3.15, (m, 1H), 3.97 (s, 3H),4.12-4.19 (m, dihydropteridin-5(6H)-yl]-2- 1H), 4.31-4.38 (m, 1H),7.10-7.13 (m, 2H), 7.36- methoxybenzonitrile 7.50 (m, 4H), 7.74 (s, 1H),8.01 (d, J = 3.0 Hz, 1H). MS(ES⁺): m/z = 515.89 [MH⁺]. HPLC: t_(R) =2.50 (ZQ3, Polar_5 min). 92 2-ethoxy-5-[(7R)-2-[(7-fluoro- ¹H NMR(CDCl₃, 300 MHz) δ: 0.98 (t, J = 6.6 Hz, 1H-indazol-5-yl)amino]-7- 6H),1.49-1.51 (m, 6H), 1.61-1.74 (m, 3H), 3.09- methyl-8-(3-methylbutyl)-6-3.15 (m, 1H), 4.15-4.23 (m, 3H), 4.31-4.35 (m,oxo-7,8-dihydropteridin-5(6H)- 1H), 7.05-7.12 (m, 2H), 7.26-7.42 (m,2H), 7.43- yl]benzonitrile 7.49 (m, 1H), 7.72(d, J = 1.5 Hz, 1H), 8.01(d, J = 2.2 Hz, 1H). MS(ES⁺): m/z = 529.88 [MH⁺]. HPLC: t_(R) = 2.65(ZQ3, Polar_5 min). 93 5-[(7R)-2-[(7-fluoro-1H- ¹H NMR (CDCl₃, 300 MHz)δ: 0.98 (t, J = 6.3 Hz, indazol-5-yl)amino]-7-methyl- 6H), 1.43-1.52 (m,9H), 1.60-1.75 (m, 3H), 3.07- 8-(3-methylbutyl)-6-oxo-7,8- 3.17, (m,1H), 4.10-4.21 (m, 1H), 4.30-4.37 (m, dihydropteridin-5(6H)-yl]-2- 1H),4.65-4.73 (m, 1H), 7.06-7.17 (m, 3H), 7.38- (propan-2-yloxy)benzonitrile7.48 (m, 3H), 7.71 (d, J = 1.8 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H).MS(ES⁺): m/z = 543.87 [MH⁺]. HPLC: t_(R) = 2.86 (ZQ3, Polar_5 min). 947-methyl-2-[(2-oxo-2,3- 1H NMR (CDCl₃, 300 MHz): δ 1.36-1.42 (m, 6H),dihydro-1H-indol-5-yl)amino]- 1.49 (d, J = 6.6 Hz, 3H), 3.50 (s, 2H),4.45 (q, J = 5-phenyl-8-(propan-2-yl)-7,8- 6.9 Hz, 1H), 4.72-4.79 (m,1H), 6.71 (d, J = 8.4 dihydropteridin-6(5H)-one Hz, 1H), 7.11(s, 1H),7.22-7.43 (m, 4H), 7.46- 7.55(m, 4H), 9.26 (brs, 1H). MS(ES⁺): m/z =429.04 [MH⁺]. HPLC: t_(R) = 2.29 (ZQ3, Polar_5 min).Example 71 was prepared by following procedure:

Step a: Synthesis of methylN-(2-chloro-5-nitropyrimidin-4-yl)-D-alaninate

To a stirred solution of 2,4-dichloro-5-nitropyrimidine (17.5 g, 90mmol) in ether (100 mL) at —OC was added a solution of D-alanine methylester hydrochloride (12 g, 85.96 mmol) in water (50 mL). To theresulting mixture was added potassium carbonate (71.2 g, 515.5 mmol) inportions with vigorous stirring. Then the reaction was allowed to warmup to rt and stirred for 16 h. The precipitated solid was filtered toafford desired product as yellow solid (4 g). Ether layer was separatedfrom filtrate, the aqueous layer was extracted with ether (50 mL×3).Combined ether layers were dried (Na₂SO₄), evaporated to give a cruderesidue, which was then purified by silica gel flash chromatography togive another 2.7 g of desired product. ¹HNMR (300 MHz, CDCl₃): δ 1.61(d, J=7.2 Hz, 3H), 3.82 (s, 3H), 4.90-5.0 (m, 1H), 8.75 (br s 1H) and9.07 (s, 1H).

Step b: synthesis of(7R)-2-chloro-7-methyl-7,8-dihydropteridin-6(5H)-one

To a stirred solution of methylN-(2-chloro-5-nitropyrimidin-4-yl)-D-alaninate (5 g, 19.2 mmol) inethanol (400 mL) was added iron powder (7.14 g, 127 mmol). The resultedmixture was heated to reflux, followed by addition of 1M aqueoushydrochloric acid (15 ml) in small portions. The mixture was refluxedfor 2 h. Then it was cooled to rt, the insoluble material was filteredoff to give a clear solution. The solvent was evaporated to give a cruderesidue, which was then purified by silica gel flash chromatography(eluent: 5% methanol in dichloromethane) to give desired product (Yield:81%). ¹HNMR (300 MHz, DMSO d₆): δ 1.34 (d, J=6.9 Hz, 3H), 4.22 (q, J=1.2Hz, 1H), 7.50 (s, 1H), 8.45 (s, 1H) and 10.59 (s, 1H).

Step c: Synthesis of3-[(7R)-2-chloro-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile

To a stirred solution of(7R)-2-chloro-7-methyl-7,8-dihydropteridin-6(5H)-one (4.2 g, 21.15 mmol)in dichloromethane (350 mL) was added triethylamine (29.61 ml, 211.5mmol), cupric acetate (7.69 g, 42.30 mmol) and 3-cyanophenyl boronicacid (6.62 g, 42.30 mmol) followed by 4 Å molecular sieves (2.0 g). Thereaction mixture was stirred for 24 h at rt with an air balloon on thetop. The reaction mixture was then filtered over celite to give a clearsolution. The solution was washed with aqueous saturated sodiumbicarbonate (50 mL×2), dried over anhydrous sodium sulfate andevaporated to give a crude material, which was purified by silica gelcolumn chromatography (eluent: 2% methanol in dichloromethane) to givethe desired product (Yield: 39%). ¹HNMR (300 MHz, CDCl₃): δ 1.66 (d,J=6.9 Hz, 3H), 4.55 (q, J=5.1 Hz, 1H), 5.98 (br s 1H), 7.16 (s, 1H),7.50-7.53 (m, 1H), 7.59-7.68 (m, 1H), 7.72 (t, J=7.8 Hz, 1H) and7.81-7.83 (m, 1H).

Step d: Synthesis of3-[(7R)-2-chloro-8-(cyclobutylmethyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile

To a stirred solution of3-[(7R)-2-chloro-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile(120 mg, 0.4 mmol) in anhydrous DMF (3 ml) was added cyclobutyl methylbromide (119 mg, 0.8 mmol) at 0° C. under nitrogen. To the resultingsolution was added sodium hydride (32 mg of 60% dispersion in oil, 0.8mmol) at 0° C. The reaction was then allowed to warm up to rt in 20 minand then heated at 50° C. for 3 h. The reaction mixture was diluted withwater (20 ml) and extracted with ethyl acetate (30 mL×3). The organiclayers were combined, dried (Na₂SO₄) and evaporated to give a cruderesidue, which was then purified by silica gel flash chromatography(eluent: 2% methanol in dichloromethane) to give desired product (Yield:41%). ¹HNMR (300 MHz, CDCl₃) δ 1.50 (d, J=6.9 Hz, 3H), 1.78-1.94 (m,4H), 1.96-2.21 (m, 2H), 2.68-2.87 (m, 1H), 3.17 (q, J=6.9 Hz, 1H),4.22-4.36 (m, 2H), 7.10 (s, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.58 (s, 1H),7.66-7.78 (m, 1H) and 7.79-7.81 (m, 1H).

Step e: Synthesis of3-[(7R)-8-(cyclobutylmethyl)-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrileExample 71

To a solution of3-[(7R)-2-chloro-8-(cyclobutylmethyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile(60 mg, 0.16 mmol) and 5-aminoindazole (22.3 mg, 0.17 mmol) intrifluoroethanol (2 mL) in a microwave reactor vial was addedtrifluoroacetic acid (55 mg). The vial was then sealed and heated in amicrowave reactor at 125° C. for 35 minutes. The reaction mixture wasthen diluted with ethyl acetate (25 mL) and washed with aqueoussaturated aq. sodium bicarbonate. The organic layer was dried (Na₂SO₄)and evaporated to give a crude residue, which was then purified bysilica gel column chromatography (eluent: 2% methanol indichloromethane) to give the desired product (Yield: 61%).

Examples 72-83 were synthesized according to procedures similar to thepreparation of Example 71, using corresponding starting materials andintermediates. For example, for the synthesis of example 72, phenylboronic acid was used in the step c of the synthesis, and(bromomethyl)cyclohexane was used in the step d of the synthesis.

Examples 84 were synthesized according to chemistry showed in thefollowing scheme. The procedures for steps a, b, c, d for synthesis ofexample 84 are similar to that of steps b, c, d, e for the preparationof Example 18, respectively.

Examples 85-94 were synthesized according to procedures similar for thepreparation of Example 1, using corresponding starting materials andintermediates. For example, for the synthesis of example 85, D-alaninemethyl ester hydrochloride was used in the step a of the synthesis;(3,4-dimethoxyphenyl)boronic acid was used in the step d of thesynthesis, and 7-fluoro-1H-indazol-5-amine was used in the step e of thesynthesis.

Ex. # Chemical Name Analytical data 95 (7R)-8-cyclohexyl-5-(3,5- ¹H NMR(CDCl₃, 300 MHz) δ 1.21-1.28 (m, 1H), difluorophenyl)-2-(1H-indazol-1.45-1.49 (m, 6H), 1.67-1.80 (m, 3H), 1.91-1.98 5-ylamino)-7-methyl-7,8-(m, 2H), 2.20-2.28 (m, 1H), 4.43-4.57 (m, 2H), dihydropteridin-6(5H)-one6.81-6.89 (m, 2H), 6.90-6.98 (m, 2H), 7.23-7.24 (m, 1H), 7.37-7.45 (m,2H), 8.00 (s, 1H), 8.16 (s, 1H), 9.99 (br s, 1H). MS(ES⁺): m/z = 490.13[MH⁺]. HPLC: t_(R) = 2.66 (ZQ3, Polar_5 min). 965-[(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ 1.18-1.24 (m, 1H),indazol-5-ylamino)-7-methyl-6- 1.46-1.52 (m, 6H), 1.63-1.81 (m, 3H),1.92-1.96 oxo-7,8-dihydropteridin-5(6H)- (m, 2H), 2.20-2.29 (m, 1H),4.39-4.49 (m, 2H), yl]-2-fluorobenzonitrile 7.08 (s, 1H), 7.16 (s, 1H),7.34-7.45 (m, 3H), 7.49- 7.54 (m, 1H), 7.56-7.59 (m, 1H), 8.01 (s, 1H),8.15 (s, 1H). MS(ES⁺): m/z = 497.12 [MH⁺]. HPLC: t_(R) = 2.61 (ZQ3,Polar_5 min). 97 3-[(7R)-2-[(7-chloro-1H- ¹H NMR (CDCl₃, 300 MHz) δ:0.85-0.87 (m, 1H), indazol-5-yl)amino]-8- 1.39-1.49 (m, 6H), 1.63-1.85(m, 3H), 1.91-1.95 cyclohexyl-7-methyl-6-oxo-7,8- (m, 2H), 2.19-2.23 (m,1H), 4.43-4.50 (m, 2H), dihydropteridin-5(6H)- 7.16 (s, 1H), 7.30 (s,1H), 7.50-7.53 (m, 1H), 7.59- yl]benzonitrile 7.66 (m, 3H), 7.72-7.75(m, 1H), 7.88 (s, 1H), 8.04 (s, 1H), 10.79 (brs, 1H). MS(ES⁺): m/z =513.12 [MH⁺]. HPLC: t_(R) = 2.79 (ZQ3, Polar_5 min). 98(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ 1.19-1.24 (m, 1H),indazol-5-ylamino)-7-methyl-5- 1.47-1.53 (m, 6H), 1.67-1.83 (m, 3H),1.89-1.96 [6-(methylsulfanyl)pyridin-3-yl]- (m, 2H), 2.22-2.30 (m, 1H),2.59 (s, 3H), 4.43-4.47 7,8-dihydropteridin-6(5H)-one (m, 2H), 7.07 (s,1H), 7.21 (s, 1H), 7.31 (dd, J = 0.6, 8.4 Hz, 1H), 7.36 (d, J = 2.4 Hz,1H), 7.39- 7.41 (m, 2H), 8.01 (s, 1H), 8.16 (s, 1H), 8.33 (s, 1H), 10.03(br s, 1H); MS(ES⁺): m/z = 501.10 [MH⁺]. 99(7R)-8-cyclohexyl-5-(3-fluoro- ¹H NMR (CDCl₃, 300 MHz) δ: 1.13-1.27 (m,1H), 5-methoxyphenyl)-2-(1H- 1.46-1.52 (m, 6H), 1.64-1.87 (m, 3H),1.91-2.01 indazol-5-ylamino)-7-methyl- (m, 2H), 2.21-2.29 (m, 1H), 3.80(s, 3H), 4.41-4.46 7,8-dihydropteridin-6(5H)-one (m, 2H), 6.56-6.59 (m,2H), 6.68-6.73 (m, 1H), 7.11 (s 1H), 7.21 (s 1H), 7.37-7.45 (m, 2H),8.01 (s, 1H), 8.16 (s, 1H), 10.10 (br s, 1H); MS(ES⁺): m/z = 502.40[MH⁺]. 100 3-[(7R)-8-cyclohexyl-2-[(4- ¹H NMR (CDCl₃, 400 MHz): δ 1.16(m, 1 H), 1.30- fluoro-1H-indazol-5-yl)amino]- 1.48 (m, 2 H), 1.49 (d, J= 6.8 Hz, 3 H), 1.64-1.74 7-methyl-6-oxo-7,8- (m, 2 H), 1.80-1.93 (m, 4H), 2.16 (d, J = 11.2 Hz, dihydropteridin-5(6H)- 1 H), 4.32 (m, 1 H),4.45 (q, J = 6.8 Hz, 1 H), 6.96 yl]benzonitrile (s, br, 1 H), 7.12 (s, 1H), 7.25 (d, J = 8.8 Hz, 1 H), 7.52 (m, 1 H), 7.59 (m, 1 H), 7.65 (t, J= 8.0 Hz, 1 H), 7.74 (dt, J = 1.2, 7.6 Hz, 1 H), 8.09 (dd, J = 7.6, 9.1Hz, 1 H), 8.13 (d, J = 1.2 Hz, 1 H), 10.22 (s, br, 1 H). MS (ES⁺): m/z =497.19 [MH⁺]. HPLC: t_(R) = 1.14 min (TOF, polar_3 min). 1013-[(7R)-2-[(4-chloro-1H- ¹H NMR (CDCl₃, 400 MHz): δ 1.19 (m, 1 H), 1.34-indazol-5-yl)amino]-8- 1.49 (m, 3 H), 1.51 (d, J = 6.8 Hz, 3 H), 1.66(m, 1 cyclohexyl-7-methyl-6-oxo-7,8- H), 1.72-1.81 (m, 2 H), 1.89-1.93(m, 1 H), 2.12 dihydropteridin-5(6H)- (d, J = 11.6 Hz, 1 H), 4.34 (m, 1H), 4.47 (q, J = yl]benzonitrile 6.8 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1H), 7.10 (s, br, 1 H), 7.14 (s, 1 H), 7.35 (m, 1 H), 7.51 (d, J = 8.0Hz, 1 H), 7.59 (m, 1 H), 7.66 (t, J = 8.4 Hz, 1 H), 7.76 (dt, J = 1.2,8.0 Hz, 1 H), 8.11 (s, 1 H), 12.40 (s, br, 1 H). MS (ES⁺): m/z = 513.16[MH⁺, ³⁵Cl], 515.18 [MH⁺, ³⁷Cl]. HPLC: t_(R) = 1.52 min (TOF, polar_3min). 102 3-[(7R)-8-cyclohexyl-2-[(4- ¹H NMR (DMSO-d₆, 400 MHz): δ 1.06(m, 1 H), methoxy-1H-indazol-5- 1.18-1.30 (m, 2 H), 1.36 (d, J = 6.4 Hz,3 H), 1.54- yl)amino]-7-methyl-6-oxo-7,8- 1.58 (m, 2 H), 1.64 (m, 1 H),1.72-1.81 (m, 3 H), dihydropteridin-5(6H)- 1.94 (d, J = 11.6 Hz, 1 H),4.11 (m, 1 H), 4.12 (s, 3 yl]benzonitrile H), 4.39 (q, J = 6.8 Hz, 1 H),6.96 (s, 1 H), 7.09 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H),7.73- 7.77 (m, 3 H), 7.84 (s, 1 H), 7.94-7.96 (m, 2 H), 8.25 (s, 1 H).MS (ES⁺): m/z = 509.20 [MH⁺]. HPLC: t_(R) = 1.08 min (TOF, polar_3 min).103 3-[(7R)-8-cyclohexyl-7-methyl- ¹H NMR (CDCl₃, 300 MHz) δ 1.12-1.19(m, 1H), 2-[(3-methyl-1H-indazol-5- 1.42-1.48 (m, 6H), 1.65-1.70 (m,3H), 1.79-1.89 yl)amino]-6-oxo-7,8- (m, 2H), 2.13-2.16 (m, 1H), 2.57 (s,3H), 4.41-4.47 dihydropteridin-5(6H)- (m, 2H), 6.88-6.95 (m, 1H), 7.15(s, 1H), 7.34-7.37 yl]benzonitrile (m, 1H), 7.45-7.53 (m, 2H), 7.59-7.66(m, 2H), 7.72-7.74 (m, 1H), 7.86 (s, 1H), 9.77 (br. s, 1H). MS(ES⁺): m/z= 493.22 (100) [MH⁺]. HPLC: t_(R) = 2.51 (ZQ3, Polar_5 min). 1045-[(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ 1.14-1.23 (m, 1H),indazol-5-ylamino)-7-methyl-6- 1.45-1.52 (m, 6H), 1.67-1.80 (m, 3H),1.93-1.95 oxo-7,8-dihydropteridin-5(6H)- (m, 2H), 2.22-2.24 (m, 1H),3.99 (s, 3H), 4.41-4.48 yl]-2-methoxybenzonitrile (m, 2H), 6.93 (s, 1H),7.09 (d, J = 9.3 Hz, 1H), 7.16 (s, 1H), 7.40-7.47 (m, 4H), 8.00 (s, 1H),8.15 (s, 1H), 10.01 (br. s, 1H). MS(ES⁺): m/z = 509.34 [MH⁺]. HPLC:t_(R) = 2.52 (ZQ3, Polar_5 min). [α]_(D) = −44.66 (C = 1.5 in CH₂Cl₂)105 2-chloro-5-[(7R)-8-cyclohexyl- ¹H NMR (CDCl₃, 300 MHz) δ 1.18-1.23(m, 1H), 2-(1H-indazol-5-ylamino)-7- 1.41-1.52 (m, 6H), 1.63-1.85 (m,3H), 1.89-2.00 methyl-6-oxo-7,8- (m, 2H), 2.20-2.28 (m, 1H), 4.39-4.49(m, 2H), dihydropteridin-5(6H)- 7.07 (s, 1H), 7.19 (s, 1H), 7.36-7.47(m, 3H), 7.61 yl]benzonitrile (d, J = 2.1 Hz, 1 H), 7.65 (d, J = 8.4 Hz,1H), 8.00 (s, 1H), 8.16 (s, 1H), 10.20 (br s, 1H). MS(ES⁺): m/z =513.25, 515.20 [MH⁺]. HPLC: t_(R) = 2.79 (ZQ3, Polar_5 min). [α]_(D) =−34.28 (C = 0.7 in CH₂Cl₂). 106 3-[(7R)-8-cyclohexyl-2-[(7- ¹H NMR(CDCl₃, 400 MHz): δ 1.22 (m, 1 H), 1.43- fluoro-1H-indazol-5-yl)amino]-1.53 (m, 2 H), 1.52 (d, J = 6.4 Hz, 3 H), 1.67-1.87 7-methyl-6-oxo-7,8-(m, 4 H), 1.94-1.96 (m, 2 H), 2.22 (d, J = 11.2 Hz,dihydropteridin-5(6H)- 1 H), 4.44 (m, 1 H), 4.49 (q, J = 6.4 Hz, 1 H),7.10 yl]benzonitrile (s, 1 H), 7.46 (dd, J = 1.6, 12.4 Hz, 1 H), 7.52(d, J = 8.0 Hz, 1 H), 7.59 (m, 1 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.72 (d,J = 2.0 Hz, 1 H), 7.77 (dt, J = 1.2, 7.6 Hz, 1 H), 8.04 (d, J = 3.2 Hz,1 H). MS (ES⁺): m/z = 497.59 [MH⁺]. HPLC: t_(R) = 0.93 min (TOF, polar_2min). 107 3-[(7R)-8-cyclohexyl-2-[(7- ¹H NMR (CDCl₃, 400 MHz): δ 1.25(m, 1 H), 1.46- fluoro-1H-indazol-4-yl)amino]- 1.53 (m, 3 H), 1.53 (d, J= 6.8 Hz, 3 H), 1.71 (m, 1 7-methyl-6-oxo-7,8- H), 1.81 (m, 1 H), 1.90(m, 1 H), 1.97-2.00 (m, 2 dihydropteridin-5(6H)- H), 2.23 (d, J = 11.2Hz, 1 H), 4.49-4.56 (m, 2 H), yl]benzonitrile 7.02 (dd, J = 8.8, 10.4Hz, 1 H), 7.58 (d, J = 7.6 Hz, 1 H), 7.67 (s, 1 H), 7.70 (t, J = 8.4 Hz,1 H), 7.80 (dt, J = 1.2, 7.6 Hz, 1 H), 8.03 (dd, J = 3.2, 8.4 Hz, 1 H),9.00 (d, J = 2.8 Hz, 1 H), 9.39 (s, 1 H). MS (ES⁺): m/z = 497.58 [MH⁺].HPLC: t_(R) = 0.97 min (TOF, polar_2 min). 108 3-[(7R)-2-[(3-chloro-1H-¹H NMR (CDCl₃, 400 MHz): δ 1.20 (m, 1 H), 1.46- indazol-5-yl)amino]-8-1.57 (m, 3 H), 1.49 (d, J = 7.2 Hz, 3 H), 1.83-1.93cyclohexyl-7-methyl-6-oxo-7,8- (m, 3 H), 2.17 (d, J = 6.4 Hz, 1 H), 4.48(q, J = 7.2 dihydropteridin-5(6H)- Hz, 1 H), 4.54 (m, 1 H), 7.18 (s, 1H), 7.38 (d, J = yl]benzonitrile 8.8 Hz, 1 H), 7.43 (dd, J = 2.4, 9.1Hz, 1 H), 7.47 (s, br, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.61 (s, 1 H),7.64 (t, J = 8.0 Hz, 1 H), 7.30 (dt, J = 1.6, 8.0 Hz, 1 H), 8.08 (d, J =1.2 Hz, 1 H), 10.85 (s, br, 1 H). MS (ES⁺): m/z = 513.57 [MH⁺, ³⁵Cl],515.55 [MH⁺, ³⁵Cl]. HPLC: t_(R) = 1.00 min (TOF, polar_2 min). 1093-[(7R)-2-(1,2-benzothiazol-5- ¹H NMR (CDCl₃, 300 MHz) δ 1.25-1.26 (m,1H), ylamino)-8-cyclohexyl-7- 1.48-1.52 (m, 6H), 1.69-1.83 (m, 3H),1.97-1.99 methyl-6-oxo-7,8- (m, 2H), 2.25-2.27 (m, 1H), 4.44-4.51 (m,2H), dihydropteridin-5(6H)- 7.05 (brs, 1H), 7.18(s, 1H), 7.51-7.54 (m,2H), yl]benzonitrile 7.59 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.74-7.76(m, 1H), 7.85 (d, J = 8.7 Hz, 1H), 8.56 (s, 1H), 8.83 (s, 1H). MS(ES⁺):m/z = 496.12 [MH⁺]. HPLC: t_(R) = 3.45 (ZQ3, Polar_5 min). [α]_(D) =−47.5 (C = 0.8 in CH₂Cl₂). 110 (7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃,300 MHz) δ 1.23-1.24 (m, 1H), indazol-5-ylamino)-5-[3- 1.47-1.53 (m,6H), 1.68-1.83 (m, 3H), 1.94-1.96 (methoxymethyl)phenyl]-7- (m, 2H),2.24-2.25(m, 1H), 3.40 (s, 3H), 4.44-4.46 methyl-7,8-dihydropteridin-(m, 2H), 4.50 (s, 2H), 6.92 (s, 1H), 7.14-7.18 (m, 6(5H)-one 2H), 7.22(s, 1H), 7.38-7.41 (m, 3H), 7.50 (t, J = 7.5 Hz, 1H), 7.99 (s, 1H), 8.17(s, 1H), 10.04 (brs, 1H). MS(ES⁺): m/z = 498.60 [MH⁺]. HPLC: t_(R) =2.51 (ZQ3, Polar_5 min). [α]_(D) = −32.22 (C = 0.9 in CH₂Cl₂). 111(7R)-8-cyclohexyl-5-(3,4- ¹H NMR (CDCl₃, 300 MHz) δ 1.19-1.25 (m, 1H),dimethoxyphenyl)-2-(1H- 1.47-1.53 (m, 6H), 1.74-1.88 (m, 3H), 1.90-1.98indazol-5-ylamino)-7-methyl- (m, 2H), 2.40-2.59 (m, 1H), 3.86 (s, 3H),3.92 (s, 7,8-dihydropteridin-6(5H)-one 3H), 4.43-4.49 (m, 2H), 6.67 (s,1H), 6.79-6.82 (m, 1H), 6.96-7.03 (m, 2H), 7.17 (s, 1H), 7.36-7.43 (m,2H), 7.99 (s, 1H), 8.17 (s, 1H), 10.10 (br s, 1H). MS(ES⁺); m/z = 514.19[MH⁺]. HPLC: t_(R) = 2.41 (ZQ3, Polar_5 min). 1123-[(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ 1.19-1.23(m, 1H),indazol-5-ylamino)-7-methyl-6- 1.45-1.52 (m, 6H), 1.66-1.80 (m, 3H),1.92-1.96 oxo-7,8-dihydropteridin-5(6H)- (m, 2H), 2.22-2.24 (m, 1H),4.42-4.49 (m, 2H), yl]-5-fluorobenzonitrile 7.04 (brs, 1H), 7.21 (s,1H), 7.28-7.32 (m, 1H), 7.37-7.45 (m, 4H), 8.01 (s, 1H), 8.15 (s, 1H),10.15(brs, 1H). MS(ES⁺): m/z = 496.75 [MH⁺]. HPLC: t_(R) = 2.68 (ZQ3,Polar_5 min). [α]_(D) = −44.0 (C = 2.0 in CH₂Cl₂) 113(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ 1.22-1.24 (m, 1H),indazol-5-ylamino)-7-methyl-5- 1.47-1.53 (m, 6H), 1.69-1.84 (m, 3H),1.94-1.96 (6-methylpyridin-3-yl)-7,8- (m, 2H), 2.25-2.27 (m, 1H), 2.64(s, 3H), 4.41-4.49 dihydropteridin-6(5H)-one (m, 2H), 7.00 (brs, 1H),7.17 (s, 1H), 7.30-7.33 (m, 1H), 7.37-7.44 (m, 2H), 7.47-7.50 (m, 1H),8.00 (s, 1H), 8.16 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H). MS(ES⁺): m/z =469.10 [MH⁺]. HPLC: t_(R) = 2.30 (ZQ3, Polar_5 min). [α]_(D) = −23.33 (C= 0.6 in CH₂Cl₂) 114 (7R)-8-cyclohexyl-2-(1H- 1H NMR (CDCl₃, 300 MHz) δ0.81-0.84 (m, 1H), indazol-5-ylamino)-7-methyl-5- 1.47-1.52 (m, 6H),1.67-1.83 (m, 3H), 1.88-1.99 [3-(methylsulfinyl)phenyl]-7,8- (m, 2H),2.20-2.26 (m, 2H), 2.78(s, 3H), 4.45-4.47 dihydropteridin-6(5H)-one (m,2H), 7.12 (s, 1H), 7.30-7.41 (m, 3H), 7.60-7.66 (m, 3H), 7.60-7.66 (m,3H), 8.00 (s, 1H), 8.15 (s, 1H). MS(ES⁺): m/z = 516.67 [MH⁺]. HPLC:t_(R) = 2.50 (ZQ3, Polar_5 min). 115 3-[(7R)-8-cyclohexyl-2-[(3- ¹H NMR(CDCl₃, 400 MHz): δ 1.22 (m, 1 H), 1.45- fluoro-1H-indazol-5-yl)amino]-1.55 (m, 3 H), 1.49 (d, J = 6.8 Hz, 3 H), 1.69 (m, 1 7-methyl-6-oxo-7,8-H), 1.74-1.86 (m, 2 H), 1.92-1.95 (m, 2 H), 2.21 dihydropteridin-5(6H)-(m, 1 H), 4.51 (m, 1 H), 4.48 (q, J = 6.8 Hz, 1 H), yl]benzonitrile 7.16(m, 1 H), 7.19 (s, br, 1 H), 7.30 (d, J = 1.6, 8.8 Hz, 1 H), 7.36 (dd, J= 2.0, 8.8 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.60 (m, 1 H), 7.66 (t,J = 8.0 Hz, 1 H), 7.75 (dt, J = 1.6, 7.6 Hz, 1 H), 8.18 (s, 1 H), 9.30(s, br, 1 H). MS (ES⁺): m/z = 497.56 [MH⁺]. HPLC: t_(R) = 0.96 min (TOF,polar_2 min). 116 3-[(7R)-8-cyclohexyl-2-[(3- ¹H NMR (CDCl₃, 400 MHz): δ1.21 (m, 1 H), 1.42- methoxy-1H-indazol-5- 1.59 (m, 3 H), 1.47 (d, J =6.8 Hz, 3 H), 1.60-1.72 yl)amino]-7-methyl-6-oxo-7,8- (m, 2 H),1.75-1.92 (m, 3 H), 2.17 (m, 1 H), 4.09 dihydropteridin-5(6H)- (s, 3 H),4.47 (q, J = 6.8 Hz, 1 H), 4.53 (m, 1 H), yl]benzonitrile 7.15 (s, 1 H),7.17 (d, J = 8.8 Hz, 1 H), 7.26 (dd, J = 1.2, 8.8 Hz, 1 H), 7.51 (d, J =8.0 Hz, 1 H), 7.56- 7.62 (m, 3 H), 7.70 (dt, J = 1.6, 7.6 Hz, 1 H), 8.14(s, 1 H), 9.48 (m, 1 H). MS (ES⁺)\ m/z = 509.53 [MH⁺]. HPLC: t_(R) =0.96 min (TOF, polar_2 min). 117 3-[(7R)-8-cyclohexyl-7-methyl- ¹H NMR(CDCl₃, 400 MHz): δ 1.08 (m, 1 H), 1.19- 2-[(4-methyl-1H-indazol-5- 1.46(m, 3 H), 1.48 (d, J = 6.8 Hz, 3 H), 1.61-1.71 yl)amino]-6-oxo-7,8- (m,2 H), 1.76-1.87 (m, 3 H), 2.07 (d, J = 11.6 Hz, dihydropteridin-5(6H)- 1H), 2.54 (s, 3 H), 4.23 (m, 1 H), 4.40 (q, J = 6.8 yl]benzonitrile Hz, 1H), 6.72 (s, br, 1 H), 7.09 (s, 1 H), 7.26 (d, J = 8.8 Hz, 1 H), 7.51(dq, J = 1.2, 8.0 Hz, 1 H), 7.59 (t, J = 2.0 Hz, 1 H), 7.60-7.64 (m, 2H), 7.71 (dt, J = 1.2, 7.2 Hz, 1 H), 8.06 (d, J = 0.8 Hz, 1 H), 10.65(s, br, 1 H). MS (ES⁺): m/z = 493.56 [MH⁺]. HPLC: t_(R) = 0.89 min (TOF,polar_2 min). 118 3-[(7R)-2-[(6-chloro-1H- ¹H NMR (CDCl₃, 400 MHz): δ1.23 (m, 1 H), 1.43- indazol-5-yl)amino]-8- 1.54 (m, 2 H), 1.51 (d, J =6.8 Hz, 3 H), 1.56-1.88 cyclohexyl-7-methyl-6-oxo-7,8- (m, 4 H),1.95-2.03 (m, 2 H), 2.22 (m, 1 H), 4.44 dihydropteridin-5(6H)- (m, 1 H),4.45 (q, J = 6.8 Hz, 1 H), 7.21 (s, br, 1 yl]benzonitrile H), 7.35 (s, 1H), 7.54 (d, J = 8.4 Hz, 1 H), 7.59- 7.62 (m, 2 H), 7.66 (t, J = 7.6 Hz,1 H), 7.76 (dt, J = 1.2, 8.0 Hz, 1 H), 8.01 (d, J = 0.8 Hz, 1 H), 8.75(s, 1 H), 10.21 (s, br, 1 H). MS (ES⁺): m/z = 513.51 [MH⁺, ³⁵Cl], 515.48[MH⁺, ³⁷Cl]. HPLC: t_(R) = 0.96 min (TOF, polar_2 min). 1193-[(7R)-8-cyclohexyl-2-[(6- ¹H NMR (CDCl₃, 400 MHz): δ 1.27 (m, 1 H),1.50 methoxy-1H-indazol-5- (d, J = 6.8 Hz, 3 H), 1.53-1.64 (m, 3 H),1.73 (m, 1 yl)amino]-7-methyl-6-oxo-7,8- H), 1.82-1.90 (m, 2 H),1.97-2.04 (m, 2 H), 2.33 dihydropteridin-5(6H)- (d, J = 11.2 Hz, 1 H),3.96 (s, 3 H), 4.50 (q, J = 6.8 yl]benzonitrile Hz, 1 H), 4.55 (m, 1 H),6.91 (s, br, 1 H), 7.21 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.60-7.62(m, 2 H), 7.65 (t, J = 8.4 Hz, 1 H), 7.74 (dt, J = 1.2, 7.6 Hz, 1 H),7.95 (s, 1 H), 8.74 (s, 1 H). MS (ES⁺): m/z = 509.55 [MH⁺]. HPLC: t_(R)= 0.92 min (TOF, polar_2 min). 120 (7R)-8-cyclohexyl-2-[(4-fluoro- ¹HNMR (CDCl₃, 300 MHz) δ 1.17-1.24 (m, 1H), 1H-indazol-5-yl)amino]-5-(3-1.41-1.47 (m, 6H), 1.62-1.78 (m, 3H), 1.82-1.95fluorophenyl)-7-methyl-7,8- (m, 2H), 2.14-2.17 (m, 1 H), 4.29-4.46 (m,2H), dihydropteridin-6(5H)-one 6.86 (s, 1H), 6.97-7.00 (m, 1H), 7.04 (d,J = 7.8 Hz, 1H), 7.12-7.17 (m, 2H), 7.22 (d, J = 9 Hz, 1H), 7.44-7.52(m, 1H), 8.10-8.16 (m, 2H), 10.23 (br s, 1H). MS(ES⁺): m/z = 490.13[MH⁺]. HPLC: t_(R) = 2.65 (ZQ3, Polar_5 min). 121(7R)-8-cyclohexyl-5-(3-fluoro- ¹H NMR (CDCl₃, 300 MHz) δ: 1.19-1.23 (m,1H), 4-methylphenyl)-2-(1H- 1.45-1.53 (m, 6H), 1.71-1.88 (m, 3H),1.90-1.99 indazol-5-ylamino)-7-methyl- (m, 2H), 2.20-2.39 (m, 1 H), 2.32(s, 3H), 4.41- 7,8-dihydropteridin-6(5H)-one 4.48 (m, 2H), 6.92-6.95 (m,2H), 7.01 (s, 1H), 7.19 (s, 1H), 7.29-7.35 (m,1H), 7.39-7.43 (m, 2H),8.00 (s, 1H), 8.17 (s, 1H), 10.19 (br s, 1H), MS(ES⁺): m/z = 486.35[MH⁺]. HPLC: t_(R) = 2.75 (ZQ3, Polar_5 min). [α]_(D) = −26.6(C = 0.6 inCH₂Cl₂) 122 (7R)-8-cyclohexyl-2-[(4-fluoro- ¹H NMR (CDCl₃, 300 MHz) δ0.80-0.90 (m, 1H), 1H-indazol-5-yl)amino]-7- 1.40-1.49 (m, 6H),1.58-1.70 (m, 3H), 1.81-1.88 methyl-5-(pyridin-3-yl)-7,8- (m, 2H),2.11-2.14 (m, 1 H), 4.27-4.33 (m, 1H), dihydropteridin-6(5H)-one4.40-4.45 (m, 1H), 6.91 (s, 1H), 7.11 (s, 1H), 7.19- 7.21 (d, J = 6.6Hz, 1H), 7.42-7.45 (m, 1H), 7.58 (d, J = 6 Hz, 1H), 8.05-8.09 (m, 2H),8.51 (s, 1H), 8.66 (d, J = 3.3 Hz, 1H). MS(ES⁺): m/z = 473.32 [MH⁺].HPLC: t_(R) = 2.22 (ZQ3, Polar_5 min). 123 3-[(7R)-8-cyclohexyl-2-[(7-¹H NMR (CDCl₃, 400 MHz): δ 1.24 (m, 1 H), 1.52 methoxy-1H-indazol-5- (d,J = 6.8 Hz, 3 H), 1.42-1.61 (m, 2 H), 1.61-1.86yl)amino]-7-methyl-6-oxo-7,8- (m, 4 H), 1.93-2.00 (m, 2 H), 2.23 (d, J =9.2 Hz, 1 dihydropteridin-5(6H)- H), 3.97 (s, 3 H), 4.42 (m, 1 H), 4.45(q, J = 6.8 yl]benzonitrile Hz, 1 H), 6.74 (d, J = 1.6 Hz, 1 H), 7.07(s, 1 H), 7.16 (s, 1 H), 7.53 (dd, J = 1.2, 8.0 Hz, 1 H), 7.61 (d, J =1.6 Hz, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.74 (dt, J = 1.2, 7.6 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1 H), 7.96 (s, 1 H), 10.48 (s, br, 1 H). MS(ES⁺): m/z = 509.48 [MH⁺]. HPLC: t_(R) = 0.90 min (TOF, polar_2 min).124 4-[(7R)-8-cyclohexyl-2-(1H- ¹H NMR (DMSO-d₆, 300 MHz) δ 0.98-1.08(m, indazol-5-ylamino)-7-methyl-6- 1H), 1.15-1.40 (m, 2H), 1.45-1.59 (m,5H), 1.61- oxo-7,8-dihydropteridin-5(6H)- 1.82 (m, 4H), 1.90-2.00 (m,1H), 4.10-4.21 (m, yl]thiophene-2-carboxylic acid 1H), 4.52-4.62 (m,1H), 7.07 (s, 1H), 7.19-7.24 (m, 1H), 7.33-7.42 (m, 1H), 7.54-7.58 (m,1H), 7.73 (s, 1H), 7.95-8.05 (s, 3H), 10.43 (br s, 1H). MS(ES⁺): 504.19[MH⁺]. HPLC: t_(R) = 2.41 (ZQ3, Polar_5 min). 125(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ 1.21-1.27 (m, 1H),indazol-5-ylamino)-5-(3- 1.45-1.53 (m, 6H), 1.68-1.83 (m, 3H), 1.91-1.98methoxy-4-methylphenyl)-7- (m, 2H), 2.24 (s, 4H), 3.80 (s, 3H),4.41-4.50 (m, methyl-7,8-dihydropteridin- 2H), 6.61 (s, 1H), 6.73 (d, J= 6.9 Hz, 1H), 6.99 (s, 6(5H)-one 1H), 7.19 (s, 1H), 7.24-7.25 (m, 1H),7.35-7.45 (m, 2H), 7.99 (s, 1H), 8.18 (s, 1H), 10.19 (br s, 1H).MS(ES⁺): m/z = 498.01 [MH⁺]. HPLC: t_(R) = 2.64 (ZQ3, Polar_5 min). 126(7R)-8-cyclohexyl-2-(1H- ¹H NMR (CDCl₃, 300 MHz) δ 1.20-1.22 (m, 1H),indazol-5-ylamino)-7-methyl-5- 1.46-1.57 (m, 6H), 1.73-1.96 (m, 5H),2.24 (br s, [4-(morpholin-4-yl)phenyl]-7,8- 1H), 3.57 (t, J = 4.2 Hz,4H), 3.84 (t, J = 4.2 Hz, dihydropteridin-6(5H)-one 4H), 4.42-4.49 (m,2H), 6.73 (d, J = 9.6 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 7.27-7.42 (m,3H), 7.99 (s, 1H), 8.05 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H). MS(ES⁺): m/z= 540.84[MH⁺]. HPLC: t_(R) = 2.40 (Polar_5 min, ZQ3). 127(7R)-8-cyclohexyl-5-[3- MS(ES⁺): m/z = 485.00 [MH⁺]. HPLC: t_(R) = 2.25(hydroxymethyl)phenyl]-2-(1H- (ZQ3, Polar_5 min).indazol-5-ylamino)-7-methyl- 7,8-dihydropteridin-6(5H)-one 1285-[(7R)-8-cyclohexyl-2-(1H- MS(ES⁺): m/z = 480.11 [MH⁺]. HPLC: t_(R) =2.45 indazol-5-ylamino)-7-methyl-6- (ZQ3, Polar_5 min).oxo-7,8-dihydropteridin-5(6H)- yl]pyridine-3-carbonitrile 129(7R)-8-cyclohexyl-5-[6- ¹H NMR (CDCl₃, 300 MHz) δ 1.15-1.19 (m, 2H),(dimethylamino)pyridin-3-yl]-2- 1.43 (d, J = 6.9 Hz, 6H), 1.70-1.79 (m,2H), 1.92- (1H-indazol-5-ylamino)-7- 1.93 (m, 2H), 2.21 (br s, 1H), 3.10(s, 3H), 3.11 (s, methyl-7,8-dihydropteridin- 3H), 4.40-4.20 (m, 2H),6.58 (d, J = 8.7 Hz, 1H), 6(5H)-one 7.15 (s, 1H), 7.26 (s, 1H),7.27-7.39 (m, 2H), 7.92 (d, J = 7.8 Hz, 2H), 8.12 (s, 1H). MS(ES⁺): m/z= 497.90 [MH⁺]. HPLC: t_(R) = 2.32 (ZQ3, Polar_5 min). 1303-[(7R)-8-cyclohexyl-2-[(4,7- ¹H NMR (CDCl₃, 400 MHz): δ 1.16 (m, 1 H),1.43- difluoro-1H-indazol-5- 1.58 (m, 3 H), 1.51 (d, J = 6.8 Hz, 3 H),1.71 (m, 1 yl)amino]-7-methyl-6-oxo-7,8- H), 1.80-1.94 (m, 4 H), 2.16(m, 1 H), 4.34 (m, 1 dihydropteridin-5(6H)- H), 4.49 (q, J = 6.8 Hz, 1H), 7.07 (d, J = 4.0 Hz, 1 yl]benzonitrile H), 7.27 (s, br, 1 H), 7.51(dd, J = 1.2, 8.4 Hz, 1 H), 7.58 (m, 1 H), 7.67 (t, J = 7.6 Hz, 1 H),7.77 (dt, J = 1.2, 7.6 Hz, 1 H), 8.02 (m, 1 H), 8.15 (d, J = 3.2 Hz, 1H), 10.21 (s, br, 1 H). MS (ES⁺): m/z = 515.39 [MH⁺]. HPLC: t_(R) = 0.97min (TOF, polar_2 min). 131 3-[(7R)-8-cyclohexyl-2-[(3,7- ¹H NMR (CDCl₃,400 MHz): δ 1.14 (m, 1 H), 1.39- difluoro-1H-indazol-5- 1.50 (m, 3 H),1.43 (d, J = 6.8 Hz, 3 H), 1.62-1.80 yl)amino]-7-methyl-6-oxo-7,8- (m, 3H), 1.86-1.89 (m, 2 H), 2.15 (m, 1 H), 4.41 dihydropteridin-5(6H)- (m, 1H), 4.42 (q, J = 6.8 Hz, 1 H), 7.71 (s, 1 H), yl]benzonitrile 7.31-7.40(m, 2 H), 7.47 (d, J = 7.2 Hz, 1 H), 7.54 (s, 1 H), 7.59 (t, J = 8.0 Hz,1 H), 7.68 (dt, J = 1.2, 8.0 Hz, 1 H), 7.70 (d, J = 2.4 Hz, 1 H), 9.83(s, br, 1 H). MS (ES⁺): m/z = 515.39 [MH⁺]. HPLC: t_(R) = 1.07 min (TOF,polar_2 min). 132 (7R)-8-cyclohexyl-5-(3,4- ¹H NMR (CDCl₃, 400 MHz): δ1.16 (m, 1 H), 1.36- dimethoxyphenyl)-2-[(7-fluoro- 1.50 (m, 2 H), 1.46(d, J = 6.8 Hz, 3 H), 1.64-1.74 1H-indazol-5-yl)amino]-7- (m, 3 H),1.79-1.90 (m, 3 H), 2.19 (m, 1 H), 3.81 methyl-7,8-dihydropteridin- (s,3 H), 3.87 (s, 3 H), 4.39 (m, 1 H), 4.42 (q, J = 6(5H)-one 6.8 Hz, 1 H),6.63 (s, 1 H), 6.75 (d, J = 7.2 Hz, 1 H), 6.92 (d, J = 8.8 Hz, 1 H),7.15 (d, J = 11.6 Hz, 1 H), 7.41 (dd, J = 1.6, 13.2 Hz, 1 H), 7.67 (d, J= 1.6 Hz, 1 H), 7.95 (d, J = 3.6 Hz, 1 H), 10.32 (s, br, 1 H). MS (ES⁺):m/z = 532.44 [MH⁺]. HPLC: t_(R) = 0.91 min (TOF, polar_2 min). 133(7R)-8-cyclohexyl-2-[(7-fluoro- ¹H NMR (400 MHz, CD₃OD): δ 8.95 (dd, J =1.5, 1H-indazol-5-yl)amino]-7- 4.3 Hz, 1H), 8.49 (d, J = 8.3 Hz, 1H),8.17 (d, J = methyl-5-(quinolin-7-yl)-7,8- 8.6 Hz, 1H), 7.96-8.02 (m,2H), 7.80 (d, J = 1.0 dihydropteridin-6(5H)-one Hz, 1H), 7.65 (dd, J =4.3, 8.3 Hz, 1H), 7.46-7.55 (m, 2H), 7.11 (s, 1H), 4.45-4.59 (m, 2H),2.22 (d, J = 11.6 Hz, 1H), 1.95 (d, J = 13.4 Hz, 2H), 1.82- 1.91 (m,2H), 1.62-1.80 (m, 2H), 1.50 (d, J = 3.3 Hz, 2H), 1.23-1.35 (m, 2H). MS(ES⁺): m/z = 523.50 [MH⁺]. UPLC: t_(R) = 0.88 min (TOF: polar_2 min).134 (7R)-8-cyclohexyl-2-[(7-fluoro- ¹H NMR (CDCl₃, 400 MHz) δ 1.04-1.29(m, 2 H) 1H-indazol-5-yl)amino]-7- 1.32-1.53 (m, 6 H) 1.58-1.82 (m, 3 H)1.87 (d, methyl-5-[4-(morpholin-4- J = 10.3 Hz, 2 H) 2.16 (d, J = 9.6Hz, 1 H) 3.44- yl)phenyl]-7,8-dihydropteridin- 3.61 (m, 4 H) 3.69-3.85(m, 4 H) 4.22-4.60 (m, 6(5H)-one 2 H) 6.69 (d, J = 8.8 Hz, 1 H) 7.09(br. s., 1 H) 7.28 (dd, J = 8.9, 2.40 Hz, 1 H) 7.39 (d, J = 12.6 Hz, 1H) 7.66 (d, J = 1.2 Hz, 1 H) 7.86-8.07 (m, 1 H). MS(ES⁺): m/z = 558.46(100 [MH⁺]. HPLC: t_(R) = 0.89 (Polar_2 min, UPLC). 135(7R)-8-cyclohexyl-2-[(7-fluoro- ¹H NMR (400 MHz, CD₃OD): δ 1.50 (d, J =6.82 1H-indazol-5-yl)amino]-7- Hz, 3H), 1.53-1.79 (m, 3H), 1.79-1.88 (m,2H), methyl-5-(pyridin-3-yl)-7,8- 1.94 (d, J = 12.3 Hz, 2H), 2.01 (s,2H), 2.20 (d, J = dihydropteridin-6(5H)-one 11.1 Hz, 1H), 4.10 (q, J =7.0 Hz, 1H), 4.49-4.59 (m, 1H), 7.09 (s, 1H), 7.49 (d, J = 12.8 Hz, 1H),7.65 (dd, J = 8.0, 4.80 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.86 (dt, J =8.2, 1.83 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 8.53 (d, J = 2.2 Hz, 1H),8.67 (dd, J = 4.9, 1.39 Hz, 1H). MS(ES⁺): m/z = 473.36[MH⁺]. HPLC: t_(R)= 0.81 min (analytical_2 min, UPLC). 136 5-[(7R)-8-cyclohexyl-2-[(7- ¹HNMR (CDCl₃, 400 MHz) δ 1.28-1.50 (m, 7 H) fluoro-1H-indazol-5-yl)amino]-1.51-1.81 (m, 4 H) 1.86 (d, J = 9.3 Hz, 2 H) 2.13 7-methyl-6-oxo-7,8-(br. s., 1 H) 3.91 (s, 3 H) 4.21-4.50 (m, 2 H) 7.02dihydropteridin-5(6H)-yl]-2- (d, J = 9.0 Hz, 1 H) 7.06 (s, 1 H) 7.24(br. s., 1 H) methoxybenzonitrile 7.31-7.44 (m, 3 H) 7.64 (d, J = 1.7Hz, 1 H) 7.93 (d, J = 3.5 Hz, 1 H). MS(ES⁺): m/z = 527.45 [MH⁺]. HPLC:t_(R) = 0.93 (Polar_2 min, ZQ3) 137 (7R)-8-cyclohexyl-2-[(7-fluoro- 1HNMR (400 MHz, CD₃OD): δ 1.28 (br. s., 1H), 1H-indazol-5-yl)amino]-5-(3-1.41-1.56 (m, 5H), 1.58-1.98 (m, 6H), 2.19 (d, J =fluorophenyl)-7-methyl-7,8- 11.1 Hz, 1H), 4.39-4.53 (m, 2H), 7.08 (s,1H), dihydropteridin-6(5H)-one 7.11-7.19 (m, 2H), 7.23-7.33 (m, 1H),7.49 (d, J = 12.8 Hz, 1H), 7.56-7.65 (m, 1H), 7.79 (d, J = 1.5 Hz, 1H),7.99 (d, J = 3.0 Hz, 1H). MS(ES⁺): m/z = 490.40 [MH⁺]. HPLC: t_(R) =0.94 (analytical_2 min, UPLC). 138 (7R)-8-cyclohexyl-2-[(7-fluoro- ¹HNMR (400 MHz, CD₃OD): δ 7.95-8.00 (m, 1H), 1H-indazol-5-yl)amino]-5-(6-7.90-7.95 (m, 1H), 7.75-7.80 (m, 1H), 7.43-7.51 methoxypyridin-3-yl)-7-(m, 1H), 7.34-7.41 (m, 1H), 7.12-7.17 (m, 1H),methyl-7,8-dihydropteridin- 6.89-6.95 (m, 1H), 4.37-4.51 (m, 2H),3.58-3.65 6(5H)-one (m, 4H), 2.14-2.23 (m, 1H), 1.87-1.96 (m, 2H),1.77-1.86 (m, 2H), 1.57-1.77 (m, 8H), 1.42-1.56 (m, 4H), 1.21-1.33 (m,2H). MS (ES⁺): m/z = 503.42 [MH⁺]. UPLC: t_(R) = 0.90 min (TOF: polar_2min). 139 (7R)-8-cyclohexyl-2-[(7-fluoro- ¹H NMR (400 MHz, CD₃OD): δ7.95-8.00 (m, 1H), 1H-indazol-5-yl)amino]-7- 7.90-7.95 (m, 1H),7.75-7.80 (m, 1H), 7.43-7.51 methyl-5-[6-(4- (m, 1H), 7.34-7.41 (m, 1H),7.12-7.17 (m, 1H), methylpiperazin-1-yl)pyridin-3- 6.89-6.95 (m, 1H),4.37-4.51 (m, 2H), 3.58-3.65 yl]-7,8-dihydropteridin-6(5H)- (m, 4H),2.14-2.23 (m, 1H), 1.87-1.96 (m, 2H), one. 1.77-1.86 (m, 2H), 1.57-1.77(m, 8H), 1.42-1.56 (m, 4H), 1.21-1.33 (m, 2H). MS (ES⁺): m/z = 571.41[MH⁺]. UPLC: t_(R) = 0.65 min (TOF: polar_2 min). 1403-[(7R)-8-cyclopentyl-7-ethyl- ¹H NMR (400 MHz, CD₃OD): δ 7.95-8.00 (m,1H), 2-(1H-indazol-5-ylamino)-6- 7.90-7.95 (m, 1H), 7.75-7.80 (m, 1H),7.43-7.51 oxo-7,8-dihydropteridin-5(6H)- (m, 1H), 7.34-7.41 (m, 1H),7.12-7.17 (m, 1H), yl]benzonitrile 6.89-6.95 (m, 1H), 4.37-4.51 (m, 2H),3.58-3.65 (m, 4H), 2.14-2.23 (m, 1H), 1.87-1.96 (m, 2H), 1.77-1.86 (m,2H), 1.57-1.77 (m, 8H), 1.42-1.56 (m, 4H), 1.21-1.33 (m, 2H). MS (ES⁺):m/z = 479.48 [MH⁺]. UPLC: t_(R) = 0.89 min (TOF: polar_2 min). 141(7R)-8-cyclohexyl-2-[(7-fluoro- ¹H NMR (400 MHz, CD₃OD): δ 7.98 (d, J =3.0 Hz, 1H-indazol-5-yl)amino]-7- 1H), 7.89 (br. s., 1H), 7.78 (d, J =1.5 Hz, 1H), methyl-5-[6-(pyrrolidin-1- 7.48 (d, J = 13.6 Hz, 1H), 7.40(d, J = 10.6 Hz, yl)pyridin-3-yl]-7,8- 1H), 7.15 (s, 1H), 6.64 (d, J =9.1 Hz, 1H), 4.41- dihydropteridin-6(5H)-one 4.52 (m, 2H), 3.46-3.53 (m,5H), 2.19 (d, J = 10.9 Hz, 1H), 2.03-2.10 (m, 4H), 1.92 (br. s., 2H),1.86 (br. s., 2H), 1.74 (d, J = 12.9 Hz, 1H), 1.59-1.67 (m, 1H), 1.50(br. s., 1H), 1.29 (s, 3H), 0.90 (dd, J = 3.4, 6.4 Hz, 1 H). MS (ES⁺):m/z = 542.40 [MH⁺]. UPLC: t_(R) = 0.78 min (TOF: polar_2 min). 142(7R)-8-cyclohexyl-2-[(7-fluoro- ¹H NMR (400 MHz, CD₃OD): δ 7.95-8.00 (m,1H), 1H-indazol-5-yl)amino]-7- 7.90-7.95 (m, 1H), 7.75-7.80 (m, 1H),7.43-7.51 methyl-5-[6-(piperidin-1- (m, 1H), 7.34-7.41 (m, 1H),7.12-7.17 (m, 1H), yl)pyridin-3-yl]-7,8- 6.89-6.95 (m, 1H), 4.37-4.51(m, 2H), 3.58-3.65 dihydropteridin-6(5H)-one (m, 4H), 2.14-2.23 (m, 1H),1.87-1.96 (m, 2H), 1.77-1.86 (m, 2H), 1.57-1.77 (m, 8H), 1.42-1.56 (m,4H), 1.21-1.33 (m, 2H). MS (ES⁺): m/z = 556.49 [MH⁺]. UPLC: t_(R) = 0.97min (TOF: polar_2 min). 143 (7R)-8-cyclohexyl-5-[6- ¹H NMR (CDCl3, 300MHz) δ 0.85-0.88 (m, 1H), (dimethylamino)pyridin-3-yl]-2- 1.46-1.53 (m,6H), 1.64-1.83 (m, 3H), 1.84-1.95 [(7-fluoro-1H-indazol-5- (m, 2H),2.21-2.32 (m, 1H), 3.13 (s, 6H), 4.43-4.47 yl)amino]-7-methyl-7,8- (m,2H), 6.59 (d, J = 9 Hz, 1H), 7.20-7.22 (m, 1H),dihydropteridin-6(5H)-one 7.28-7.29 (m, 1H), 7.46 (dd, J = 12.6, 1.5 Hz,1H), 7.72 (d, J = 1.8 Hz, 1H), 8.01 (br s, 2H). MS(ES⁺): m/z = 515.47(60) [MH+]. HPLC: t_(R) = 2.27 (ZQ3, Polar_5 min). 1443-[(7R)-8-cyclohexyl-2-[(3,4- ¹H NMR (CDCl₃, 400 MHz): δ 1.18 (m, 1 H),1.34- difluoro-1H-indazol-5- 1.52 (m, 3 H), 1.48 (d, J = 6.4 Hz, 3 H),1.66-1.74 yl)amino]-7-methyl-6-oxo-7,8- (m, 2 H), 1.80 (m, 1 H),1.87-1.93 (m, 2 H), 2.15 dihydropteridin-5(6H)- (m, 1 H), 4.33 (m, 1 H),4.45 (q, J = 6.8 Hz, 1 H), yl]benzonitrile 6.96 (s, 1 H), 7.08 (dd, J =2.0, 9.2 Hz, 1 H), 7.12 (s, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.58 (s, 1H), 7.64 (t, J = 8.0 Hz, 1 H), 7.73 (dt, J = 1.8, 8.0 Hz, 1 H), 8.10(dd, J = 6.8, 8.4 Hz, 1 H), 9.62 (s, br, 1 H). MS (ES⁺): m/z = 515.39[MH⁺]. HPLC: t_(R) = 0.94 min (TOF, polar_2 min). 1453-[(7R)-8-cyclohexyl-2-[(7- ¹H NMR (CDCl₃, 400 MHz): δ 1.23 (m, 1 H),1.47- fluoro-2-oxo-2,3-dihydro-1H- 1.52 (m, 3 H), 1.48 (d, J = 6.4 Hz, 3H), 1.69 (m, 1 indol-5-yl)amino]-7-methyl-6- H), 1.77-1.86 (m, 2 H),1.90-1.95 (m, 2 H), 2.21 oxo-7,8-dihydropteridin-5(6H)- (m, 1 H), 3.57(s, 2 H), 4.43 (m, 1 H), 4.47 (q, J = yl]benzonitrile 6.8 Hz, 1 H), 7.14(s, 1 H), 7.15 (d, J = 2.8 Hz, 1 H), 7.21 (d, J = 0.8 Hz, 1 H),7.51-7.53 (m, 2 H), 7.58 (m, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.75 (dt,J = 1.2, 7.6 Hz, 1 H), 8.32 (s, br, 1 H). MS (ES⁺): m/z = 512.39 [MH⁺].HPLC: t_(R) = 0.88 min (TOF, polar_2 min). 1463-[(7R)-8-cyclohexyl-7-methyl- ¹H NMR (CDCl₃, 400 MHz): δ 1.16 (m, 1 H),1.43- 6-oxo-2-[(3,4,7-trifluoro-1H- 1.58 (m, 3 H), 1.50 (d, J = 6.8 Hz,3 H), 1.74 (m, 1 indazol-5-yl)amino]-7,8- H), 1.81-1.93 (m, 4 H), 2.17(m, 1 H), 4.40 (m, 1 dihydropteridin-5(6H)- H), 4.47 (q, J = 7.2 Hz, 1H), 6.89 (m, 1 H), 7.15 yl]benzonitrile (s, 1 H), 7.52 (dd, J = 1.2, 8.4Hz, 1 H), 7.59 (m, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.75 (dt, J = 1.2,7.6 Hz, 1 H), 8.27 (dd, J = 5.2, 12.0 Hz, 1 H), 9.23 (s, br, 1 H). MS(ES⁺): m/z = 533.35 [MH⁺]. HPLC: t_(R) = 1.06 min (TOF, polar_2 min).147 (7R)-8-cyclohexyl-2-[(7-fluoro- ¹H NMR (400 MHz, CDCl₃): δ 7.95-8.09(m, 2H), 1H-indazol-5-yl)amino]-5-[6-(4- 7.71-7.76 (m, 1H), 7.43-7.51(m, 1H), 7.04-7.26 hydroxypiperidin-1-yl)pyridin-3- (m, 2H), 6.78 (d, J= 9.1 Hz, 1H), 4.34-4.57 (m, yl]-7-methyl-7,8- 3H), 3.92-4.18 (m, 3H),3.31 (ddd, J = 3.2, 9.7, dihydropteridin-6(5H)-one. 13.2 Hz, 2H),2.16-2.28 (m, 1H), 1.85-2.06 (m, 6H), 1.69-1.82 (m, 3H), 1.60-1.68 (m,3H), 1.38- 1.54 (m, 6H). MS (ES⁺): m/z = 572.34 [MH⁺]. UPLC: t_(R) =0.82 min (TOF: polar_2 min). 148 4-{[(7R)-8-cyclohexyl-5-(3,4- ¹H NMR(CD₃OD and CDCl₃, 300 MHz) δ: 1.20- dimethoxyphenyl)-7-methyl-6- 1.26(m, 1H), 1.44-1.57 (m, 6H), 1.72-1.81 (m,oxo-5,6,7,8-tetrahydropteridin- 3H), 1.90-1.94 (m, 2H), 2.21-2.22 (m,1H), 3.79 2-yl]amino}benzoic acid (s, 3H), 3.86 (s, 3H), 4.41-4.46 (m,2H), 6.73-6.78 (m, 2H), 7.01-7.06 (m, 2H), 7.66-7.70 (m, 2H), 7.88 (d, J= 8.7 Hz, 2H). MS (ES⁺): m/z = 517.73 [MH⁺]. UPLC: t_(R) = 2.68 min(ZQ3: polar_5 min). 149 3-[(7R)-8-cyclohexyl-7-methyl- ¹H NMR (400 MHz,CD₃OD): δ 7.83-7.90 (m, 2H), 6-oxo-2-[(2-oxo-2,3-dihydro- 7.71-7.80 (m,2H), 7.64 (d, J = 8.3 Hz, 1H), 7.20 1,3-benzoxazol-6-yl)amino]- (dd, J =2.0, 8.6 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J = 7,8-dihydropteridin-(6H)-8.3 Hz, 1H), 4.50 (d, J = 6.8 Hz, 2H), 2.14-2.24 yl]benzonitrile (m,2H), 1.94 (d, J = 12.4 Hz, 2H), 1.80-1.87 (m, 2H), 1.76 (d, J = 13.1 Hz,1H), 1.46-1.70 (m, 6H). MS (ES⁺): m/z = 496.31 [MH⁺]. UPLC: t_(R) = 0.87min (TOF: polar_2 min). 150 (7R)-8-cyclohexyl-5-(3,4- ¹H NMR (400 MHz,CD₃OD): δ 7.85 (d, J = 2.0 dimethoxyphenyl)-7-methyl-2- Hz, 1H), 7.19(dd, J = 2.0, 8.3 Hz, 1H), 7.11 (d, J = [(2-oxo-2,3-dihydro-1,3- 8.3 Hz,1H), 7.07 (s, 1H), 6.97 (d, J = 8.3 Hz, benzoxazol-6-yl)amino]-7,8- 1H),6.76-6.88 (m, 2H), 4.36-4.52 (m, 2H), 3.89 (s, dihydropteridin-6(5H)-one3H), 3.82 (s, 3H), 2.20 (d, J = 10.9 Hz, 1H), 1.94 (d, J = 10.1 Hz, 2H),1.72-1.87 (m, 3H), 1.58 (br. s., 6H), 1.23-1.35 (m, 1 H). MS (ES⁺): m/z= 531.35 [MH⁺]. UPLC: t_(R) = 0.84 min (TOF: polar_2 min). 151(7R)-8-cyclohexyl-7-methyl-2- ¹H NMR (400 MHz, CD₃OD): δ 8.66 (dd, J =1.5, [(2-oxo-2,3-dihydro-1,3- 4.8 Hz, 1H), 8.52 (d, J = 2.3 Hz, 1H),7.82-7.88 benzoxazol-6-yl)amino]-5- (m, 2H), 7.65 (dd, J = 4.9, 8.2 Hz,1H), 7.20 (dd, J = (pyridin-3-yl)-7,8- 2.0, 8.6 Hz, 1H), 7.08 (s, 1H),6.97 (d, J = 8.6 dihydropteridin-6(5H)-one Hz, 1H), 4.40-4.57 (m, 2H),2.20 (d, J = 11.1 Hz, 1H), 1.95 (d, J = 11.4 Hz, 2H), 1.72-1.88 (m, 3H),1.65 (d, J = 12.6 Hz, 1H), 1.47-1.61 (m, 5H), 1.26- 1.32 (m, 1H). MS(ES⁺): m/z = 472.29 [MH⁺]. UPLC: t_(R) = 0.75 min (TOF: polar_2 min).152 3-[(7R)-8-cyclohexyl-7-methyl- ¹H NMR (400 MHz, CD₃OD): δ 8.63 (d, J= 2.0 Hz, 6-oxo-2-(1H-pyrazolo[3,4- 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.01(s, 1H), 7.88 (d, b]pyridin-5-ylamino)-7,8- J = 7.6 Hz, 1H), 7.72-7.80(m, 2H), 7.61-7.68 (m, dihydropteridin-5(6H)- 1H), 7.07 (s, 1H), 4.50(q, J = 6.7 Hz, 1H), 4.38 yl]benzonitrile (br. s., 1H), 2.15 (s, 1H),1.78-1.95 (m,4H), 1.56- 1.76 (m, 2H), 1.37-1.52 (m, 5H), 1.20-1.29 (m,1H). MS (ES⁺): m/z = 480.31 [MH⁺]. UPLC: t_(R) = 0.83 min (TOF: polar_2min). 153 (7R)-8-cyclohexyl-5-(3,4- ¹H NMR (400 MHz, CD₃OD): δ 8.48-8.65(m, 2H), dimethoxyphenyl)-7-methyl-2- 8.01 (s, 1H), 7.04-7.15 (m, 2H),6.86 (br. s., 2H), (1H-pyrazolo[3,4-B]pyridin-5- 4.47 (d, J = 6.6 Hz,1H), 4.37 (br. s., 1H), 3.90 (s, ylamino)-7,8-dihydropteridin- 3H), 3.83(s, 3H), 2.15 (d, J = 12.4 Hz, 1H), 1.77- 6(5H)-one. 1.95 (m, 4H),1.57-1.76 (m, 2H), 1.37-1.52 (m, 5H), 1.28 (br. s., 1H). MS (ES⁺): m/z =515.35 [MH⁺]. UPLC: t_(R) = 0.80 min (TOF: polar_2 min). 154(7R)-8-cyclohexyl-7-methyl-2- ¹H NMR (400 MHz, CD₃OD): δ 8.65-8.69 (m,1H), (1H-pyrazolo[3,4-b]pyridin-5- 8.63 (d, J = 2.3 Hz, 1H), 8.51-8.55(m, 2H), 8.01 ylamino)-5-(pyridin-3-yl)-7,8- (s, 1H), 7.86 (td, J = 1.1,8.1 Hz, 1H), 7.65 (dd, J = dihydropteridin-6(5H)-one 4.8, 8.1 Hz, 1H),7.09 (d, J = 1.0 Hz, 1H), 4.51 (d, J = 6.8 Hz, 1H), 4.33-4.45 (m, 1H),2.15 (br. s., 1H), 1.78-1.97 (m, 4H), 1.71 (d, J = 1.0 Hz, 3H),1.38-1.52 (m, 5H). MS (ES⁺): m/z = 456.45 [MH⁺]. UPLC: t_(R) = 0.67 min(TOF: polar_2 min) 155 4-{[(7R)-5-(3-cyanophenyl)-8- ¹H NMR (400 MHz,CD₃OD): δ 7.85-7.95 (m, 3H), cyclohexyl-7-methyl-6-oxo- 7.71-7.81 (m,4H), 7.65 (d, J = 8.1 Hz, 1H), 7.11 5,6,7,8-tetrahydropteridin-2- (s,1H), 4.41-4.58 (m, 2H), 2.24 (br. s., 1H), 1.92- yl]amino}benzoic acid.2.03 (m, 2H), 1.75-1.89 (m, 3H), 1.47-1.72 (m, 6H), 1.26-1.36 (m, 1 H).MS (ES⁺): m/z = 483.09 [MH⁺]. UPLC: t_(R) = 1.01 min (TOF: polar_2 min).156 3-[(7R)-8-cyclohexyl-7-methyl- ¹H NMR (400 MHz, CD₃OD) δ 7.87 (d, J= 7.8 Hz, 6-oxo-2-(phenylamino)-7,8- 1H), 7.71-7.80 (m, 2H), 7.55-7.67(m, 3H), 7.26 (t, dihydropteridin-5(6H)- J = 7.3 Hz, 2H), 6.88-7.09 (m,2H), 4.37-4.56 (m, yl]benzonitrile 2H), 2.21 (d, J = 11.4 Hz, 1H), 1.95(d, J = 11.9 Hz, 2H), 1.72-1.87 (m, 2H), 1.59-1.69 (m, 1H), 1.44-1.54(m, 5H), 1.30 (d, J = 12.1 Hz, 2H). MS (ES⁺): m/z = 439.17 [M + H]⁺.UPLC: t_(R) = 1.11 min (TOF: polar_2 min). 1575-{[(7R)-5-(3-cyanophenyl)-8- ¹H NMR (400 MHz, CD₃OD): δ 8.19-8.23 (m,1H), cyclohexyl-7-methyl-6-oxo- 7.83-7.90 (m, 1H), 7.71-7.81 (m, 2H),7.61-7.68 5,6,7,8-tetrahydropteridin-2- (m, 1H), 7.51-7.59 (m, 2H), 7.12(s, 1H), 4.51 (q, J = yl]amino}-1H-indazole-3- 6.8 Hz, 2H), 2.11-2.21(m, 1H), 1.69-1.94 (m, carbonitrile. 5H), 1.44-1.67 (m, 6H), 1.19-1.28(m, 1H). MS (ES⁺): m/z = 504.30 [MH⁺]. UPLC: t_(R) = 0.97 min (TOF:polar_2 min). 158 3-[(7R)-8-cyclohexyl-2-[(3,5- ¹H NMR (400 MHz, CD₃OD):δ 7.86 (d, J = 7.8 Hz, difluoro-4- 1H), 7.68-7.79 (m, 2H), 7.62 (d, J =7.6 Hz, 1H), hydroxyphenyl)amino]-7- 7.22-7.32 (m, 2H), 7.05 (s, 1H),4.40-4.53 (m, 2H), methyl-6-oxo-7,8- 2.19 (d, J = 10.6 Hz, 1H), 1.92(br. s., 2H), 1.69- dihydropteridin-5(6H)- 1.86 (m, 3H), 1.42-1.68 (m,6H), 1.21-1.37 (m, yl]benzonitrile 1H). MS (ES⁺): m/z = 490.96 [MH⁺].UPLC: t_(R) = 1.00 min (TOF: polar_2 min). 159(7R)-8-cyclohexyl-2-[(3,5- ¹H NMR (400 MHz, CD₃OD): δ 7.22-7.32 (m, 2H),difluoro-4- 7.05-7.13 (m, 2H), 6.75-6.88 (m, 2H), 4.47 (q, J =hydroxyphenyl)amino]-5-(3,4- 6.7 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 3H),2.18 (t, J = dimethoxyphenyl)-7-methyl- 11.0 Hz, 1H), 1.88-1.98 (m, 2H),1.71-1.86 (m, 7,8-dihydropteridin-6(5H)-one 3H), 1.43-1.66 (m, 6H), 1.30(dd, J = 3.3, 12.6 Hz, 1H). MS (ES⁺): m/z = 526.21 [MH⁺]. UPLC: t_(R) =0.94 min (TOF: polar_2 min). 160 (7R)-8-cyclohexyl-2-[(3,5- ¹H NMR (400MHz, CD₃OD): δ 8.66 (dd, J = 1.5, difluoro-4- 4.8 Hz, 1H), 8.52 (d, J =2.3 Hz, 1H), 7.84 (td, J = hydroxyphenyl)amino]-7- 1.8, 8.2 Hz, 1H),7.64 (dd, J = 4.9, 8.2 Hz, 1H), methyl-5-(pyridin-3-yl)-7,8- 7.22-7.32(m, 2H), 7.08 (s, 1H), 4.43-4.55 (m, 2H), dihydropteridin-(5H)-one. 2.20(d, J = 11.9 Hz, 1H), 1.88-1.99 (m, 2H), 1.71- 1.86 (m, 3H), 1.45-1.70(m, 6H), 1.25-1.34 (m, 1H). MS (ES⁺): m/z = 467.35 [MH⁺]. UPLC: t_(R) =0.86 min (TOF: polar_2 min). 161 3-[(7R)-8-cyclohexyl-7-methyl- ¹H NMR(400 MHz, CD₃OD): δ 8.04 (d, J = 0.8 Hz, 6-oxo-2-[(1-oxo-2,3-dihydro-1H), 7.85-7.90 (m, 1H), 7.73-7.81 (m, 2H), 7.62-1H-isoindol-5-yl)amino]-7,8- 7.71 (m, 3H), 7.39-7.52 (m, J = 6.6 Hz,1H), 7.20- dihydropteridin-5(6H)- 7.42 (m, 1H), 7.13 (s, 1H), 4.53 (q, J= 6.8 Hz, yl]benzonitrile 2H), 2.23 (d, J = 10.6 Hz, 1H), 1.92-2.03 (m,2H), 1.74-1.88 (m, 3H), 1.60-1.73 (m, 1H), 1.45-1.59 (m, 5H), 1.29 (br.s., 1H). MS (ES⁺): m/z = 494.34 [MH⁺]. UPLC: t_(R) = 0.88 min (TOF:polar_2 min). 162 (7R)-8-cyclohexyl-5-(3,4- ¹H NMR (400 MHz, CD₃OD): δ8.43 (d, J = 5.3 Hz, dimethoxyphenyl)-7-methyl-2- 2H), 7.38 (d, J = 5.8Hz, 2H), 7.09 (d, J = 8.6 Hz, [(pyridin-4-ylmethyl)amino]- 1H), 6.93 (s,1H), 6.70-6.85 (m, 2H), 4.56 (s, 2H), 7,8-dihydropteridin-6(5H)-one 4.36(q, J = 6.8 Hz, 1H), 4.06 (br. s., 1H), 3.88 (s, 3H), 3.81 (s, 3H),1.72-1.90 (m, 4H), 1.58-1.69 (m, 2H), 1.43-1.57 (m, 1H), 1.40 (d, J =6.6 Hz, 3H), 1.13-1.34 (m, 3H). MS (ES⁺): m/z = 489.81 [MH⁺]. UPLC:t_(R) = 0.61 min (TOF: polar_2 min). 163 (7R)-8-cyclohexyl-5-(3,4- ¹HNMR (400 MHz, CD₃OD): δ 7.53 (br. s., 2H), dimethoxyphenyl)-7-methyl-2-7.09 (d, J = 8.1 Hz, 1H), 6.93 (s, 1H), 6.81 (br. s., [(1H-pyrazol-4-2H), 4.30-4.45 (m, 4H), 3.88 (s, 3H), 3.80 (s, 3H), ylmethyl)amino]-7,8-2.08 (d, J = 10.6 Hz, 1H), 1.57-1.94 (m, 6H), 1.44dihydropteridin-6(5H)-one. (d, J = 5.8 Hz, 5H), 1.20-1.32 (m, 1H). MS(ES⁺): m/z = 478.73 [MH⁺]. UPLC: t_(R) = 0.78 min (TOF: polar_2 min).164 5-[(7R)-8-cyclohexyl-7-methyl- ¹H NMR (400 MHz, CD₃OD): δ 8.62 (d, J= 2.3 Hz, 6-oxo-2-(1H-pyrazolo[3,4- 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.01(s, 1H), 7.65 (d, b]pyridin-5-ylamino)-7,8- J = 2.3 Hz, 1H), 7.56 (d, J= 6.8 Hz, 1H), 7.36 (d, dihydropteridin-5(6H)-yl]-2- J = 8.8 Hz, 1H),7.09 (s, 1H), 4.48 (q, J = 6.7 Hz, methoxybenzonitrile. 1H), 4.37 (br.s., 1H), 4.03 (s, 3H), 2.14 (d, J = 11.4 Hz, 1H), 1.76-1.95(m,4H), 1.71(d, J = 12.6 Hz, 1H), 1.62 (dd, J = 3.3, 12.1 Hz, 1H), 1.37-1.50 (m,5H), 1.17-1.30 (m, 1H). MS (ES⁺): m/z = 510.39 [MH⁺]. UPLC: t_(R) = 0.83min (TOF: polar_2 min). 165 5-[(7R)-8-cyclohexyl-7-methyl- ¹H NMR (400MHz, CD₃OD): δ 7.85 (s, 1H), 7.64 6-oxo-2-[(2-oxo-2,3-dihydro- (br. s.,1H), 7.55 (d, J = 9.9 Hz, 1H), 7.35 (d, J = 1,3-benzoxazol-6-yl)amino]-9.1 Hz, 1H), 7.14-7.21 (m, 1H), 7.07 (s, 1H), 6.977,8-dihydropteridin-5(6H)-yl]-2- (d, J = 8.3 Hz, 1H), 4.37-4.52 (m, 2H),4.03 (s, methoxybenzonitrile 3H), 2.19 (d, J = 11.6 Hz, 1H), 1.94 (d, J= 10.1 Hz, 2H), 1.70-1.87 (m, 3H), 1.59-1.66 (m, 1H), 1.47 (d, J = 6.8Hz, 5H), 1.28 (d, J = 12.6 Hz, 1H). MS (ES⁺): m/z = 526.38 [MH⁺]. UPLC:t_(R) = 0.87 min (TOF: polar_2 min). 166 3-[(7R)-8-cyclohexyl-7-methyl-¹H NMR (400 MHz, CD₃OD): δ 7.83-7.90 (m, 1 H),6-oxo-2-[(3-oxo-2,3-dihydro- 7.70-7.80 (m, 2H), 7.59-7.67 (m, 2H), 7.48(d, J = 1,2-benzoxazol-6-yl)amino]- 2.0 Hz, 1H), 7.11 (s, 1H), 7.05 (dd,J = 2.1, 8.7 7,8-dihydropteridin-5(6H)- Hz, 1H), 4.48-4.60 (m, 2H), 2.24(br. s., 1H), 1.90- yl]benzonitrile 1.99 (m, 2H), 1.72-1.87 (m, 3H),1.60-1.71 (m, 2H), 1.49 (d, J = 6.6 Hz, 3H), 1.25-1.34 (m, 2H). MS(ES⁺): m/z = 496.78 [MH⁺]. UPLC: t_(R) = 0.99 min (TOF: polar_2 min).167 3-[(7R)-8-cyclohexyl-7-methyl- ¹H NMR (CDCl₃, 400 MHz): δ 1.25 (m, 1H), 1.49 6-oxo-2-(1H-pyrazolo[4,3- (d, J = 6.8 Hz, 3 H), 1.42-1.56 (m, 2H), 1.67-1.87 b]pyridin-5-ylamino)-7,8- (m, 4 H), 1.94-1.99 (m, 2 H),2.25 (d, J = 9.2 Hz, 1 dihydropteridin-5(6H)- H), 4.38 (m, 1 H), 4.49(q, J = 6.8 Hz, 1 H), 7.30 yl]benzonitrile (s, 1 H), 7.54 (d, J = 8.0Hz, 1 H), 7.61-7.66 (m, 2 H), 7.72 (dt, J = 1.2, 7.6 Hz, 1 H), 7.81 (d,J = 9.2 Hz, 1 H), 8.06 (s, 1 H), 8.48 (d, J = 9.2 Hz, 1 H), 8.68 (s, 1H), 11.11 (s, br, 1 H). MS (ES⁺): m/z = 480.60 [MH⁺]. HPLC: t_(R) = 0.84min (TOF, polar_2 min). 168 3-[(7R)-8-cyclohexyl-2-[(5- ¹H NMR (DMSO-d₆,400 MHz): δ 1.26 (m, 1 H), hydroxypyridin-2-yl)amino]-7- 1.39 (d, J =6.8 Hz, 3 H), 1.37-1.48 (m, 2 H), 1.62- methyl-6-oxo-7,8- 1.75 (m, 4 H),1.85-1.88 (m, 2 H), 2.08 (d, J = 10.8 dihydropteridin-5(6H)- Hz, 1 H),4.28 (m, 1 H), 4.46 (q, J = 6.8 Hz, 1 H), yl]benzonitrile 7.07 (d, J =1.2 Hz, 1 H), 7.15 (dd, J = 3.2, 9.2 Hz, 1 H), 7.71-7.79 (m, 2 H), 7.81(d, J = 2.4 Hz, 1 H), 7.96-8.00 (m, 3 H), 9.03 (s, 1 H), 9.36 (d, J =0.8 Hz, 1 H). MS (ES⁺): m/z = 456.62 [MH⁺]. HPLC: t_(R) = 0.85 min (TOF,polar_2 min). 169 3-[(7R)-8-cyclohexyl-2-[(4- ¹H NMR (400 MHz, CD₃OD): δ1.31 (d, J = 12.63 fluoro-2-oxo-2,3-dihydro-1,3- Hz, 1H), 1.42-1.71 (m,6H), 1.73-1.88 (m, 3H), benzoxazol-6-yl)amino]-7- 1.96 (d, J = 10.86 Hz,2H), 2.22 (d, J = 10.86 Hz, methyl-6-oxo-7,8- 1H), 4.41-4.58 (m, 2H),7.09 (s, 1H), 7.36 (d, J = dihydropteridin-5(6H)- 12.63 Hz, 1H), 7.55(s, 1H), 7.65 (d, J = 7.83 Hz, yl]benzonitrile 1H), 7.71-7.76 (m, 1H),7.77-7.81(m, 1H), 7.88 (dd, J = 7.83, 1.01 Hz, 1H). MS(ES⁺): m/z =514.64[MH⁺]. HPLC: t_(R) = 0.98 min (analytical_2 min, UPLC). 170(7R)-8-cyclohexyl-5-(3,4- ¹H NMR (400 MHz, CD₃OD): δ 8.44 (br. s., 1H),dimethoxyphenyl)-7-methyl-2- 7.75 (br. s., 1H), 7.26 (br. s., 1H), 7.14(d, J = 7.6 {[2-(1H-pyrazol-4- Hz, 1H), 6.89 (br. s., 2H), 4.59 (br. s.,2H), 3.91 (s, yl)ethyl]amino}-7,8- 3H), 3.83 (br. s., 3H), 3.21 (q, J =7.3 Hz, 3H), dihydropteridin-6(5H)-one. 2.94 (br. s., 2H), 2.17 (d, J =9.9 Hz, 1H), 1.91- 1.98 (m, 3H), 1.87 (br. s., 1H), 1.77 (d, J = 12.6Hz, 2H), 1.54 (d, J = 6.6 Hz, 3H), 1.31 (t, J = 7.3 Hz, 2H). MS (ES⁺):m/z = 492.37 [MH⁺]. UPLC: t_(R) = 0.77 min (TOF: polar_2 min). 1713-[(7R)-8-cyclohexyl-2-{[4- ¹H NMR (CDCl₃, 400 MHz): δ 1.24 (m, 1 H),1.48 (hydroxymethyl)phenyl]amino}- (d, J = 6.8 Hz, 3 H), 1.42-1.53 (m, 2H), 1.65-1.86 7-methyl-6-oxo-7,8- (m, 4 H), 1.95-1.97 (m, 2 H), 2.25 (d,J = 5.6 Hz, 1 dihydropteridin-5(6H)- H), 4.42 (m, 1 H), 4.47 (q, J = 6.8Hz, 1 H), 4.64 yl]benzonitrile (s, 2 H), 7.13 (s, 2 H), 7.30 (d, J = 8.0Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.56-7.59 (m, 3 H), 7.64 (t, J =8.0 Hz, 1 H), 7.74 (dt, J = 0.8, 7.6 Hz, 1 H). MS (ES⁺): m/z = 469.80[MH⁺]. HPLC: t_(R) = 0.91 min (TOF, polar_2 min). 1723-[(7R)-8-cyclohexyl-7-methyl- ¹H NMR (CDCl₃, 400 MHz): δ 1.23 (m, 1 H),1.42- 6-oxo-2-[(2-oxo-2,3- 1.54 (m, 2 H), 1.53 (d, J = 6.8 Hz, 3 H),1.66-1.76 dihydro[1,3]oxazolo[4,5- (m, 2 H), 1.80-1.88 (m, 2 H),1.96-1.99 (m, 2 H), b]pyridin-6-yl)amino]-7,8- 2.26 (m, 1 H), 4.41 (m, 1H), 4.53 (q, J = 6.8 Hz, 1 dihydropteridin-5(6H)- H), 7.22 (s, 1 H),7.26 (s, 1 H), 7.57 (d, J = 8.0 Hz, yl]benzonitrile 1 H), 7.60 (s, 1 H),7.69 (t, J = 7.6 Hz, 1 H), 7.78 (dt, J = 1.2, 7.6 Hz, 1 H), 8.13 (d, J =2.0 Hz, 1 H), 8.57 (d, J = 2.0 Hz, 1 H), 9.13 (s, br, 1 H). MS (ES⁺):m/z = 497.35 [MH⁺]. HPLC: t_(R) = 0.92 min (TOF, polar_2 min). 1735-[(7R)-8-cyclohexyl-2-[(7- ¹H NMR (CDCl₃, 400 MHz): δ 1.24 (m, 1 H),1.48 fluoro-1H-indazol-5-yl)amino]- (d, J = 6.8 Hz, 3 H), 1.49-1.53 (m,2 H), 1.69-1.87 7-methyl-6-oxo-7,8- (m, 4 H), 1.94-2.00 (m, 2 H), 2.25(m, 1 H), 2.41 dihydropteridin-5(6H)-yl]-2-(4- (s, 3 H), 2.69 (t, J =4.8 Hz, 4 H), 3.35 (t, J = 4.8 methylpiperazin-1- Hz, 4 H), 4.45 (m, 1H), 4.48 (q, J = 6.8 Hz, 1 H), yl)benzonitrile 7.11 (d, J = 9.2 Hz, 1H), 7.20 (s, 1 H), 7.35 (dd, J = 1.6, 8.8 Hz, 1 H), 7.40 (s, 1 H), 7.42(dd, J = 1.6, 12.8 Hz, 1 H), 7.46 (d, J = 1.6 Hz, 1 H), 7.76 (d, J = 1.6Hz, 1 H), 8.03 (d, J = 2.8 Hz, 1 H), 11.31 (s, br, 1 H). MS (ES⁺): m/z =595.43 [MH⁺]. HPLC: t_(R) = 0.74 min (TOF, polar_2 min). 1743-[(7R)-8-cyclohexyl-2-[(2,2- ¹H NMR (400 MHz, CD₃OD): δ 7.86 (d, J =7.8 Hz, dioxido-1,3-dihydro-2,1- 1H), 7.71-7.79 (m, 2H), 7.63 (d, J =8.1 Hz, 1H), benzothiazol-5-yl)amino]-7- 7.57 (d, J = 1.0 Hz, 1H), 7.46(dd, J = 1.5, 8.6 Hz, methyl-6-oxo-7,8- 1H), 7.02 (s, 1H), 6.81 (d, J =8.6 Hz, 1H), 4.39- dihydropteridin-5(6H)- 4.52 (m, 2H), 2.15 (d, J =10.1 Hz, 1H), 1.89-1.98 yl]benzonitrile. (m, 2H), 1.57-1.86 (m, 5H),1.47 (d, J = 6.8 Hz, 5H), 0.87-0.92 (m, 2H). MS (ES⁺): m/z =530.41[MH⁺]. UPLC: t_(R) = 0.88 min (TOF: polar_2 min). 175(7R)-8-cyclohexyl-7-methyl-5- ¹H NMR (400 MHz, CD₃OD): δ 7.99 (br. s.,1H), (1-methyl-2-oxo-1,2- 7.87 (d, J = 8.3 Hz, 1H), 7.71-7.81 (m, 3H),7.65 dihydropyridin-4-yl)-2-(1H- (d, J = 8.6 Hz, 1H), 7.50 (d, J = 13.6Hz, 1H), 7.08 pyrazolo[3,4-b]pyridin-5- (s, 1H), 4.49-4.63 (m, 2H), 2.19(d, J = 10.9 Hz, ylamino)-7,8-dihydropteridin- 1H), 1.93-2.08 (m, 3H),1.73-1.84 (m, 2H), 1.50 6(5H)-one (d, J = 6.6 Hz, 3H), 1.00-1.10 (m,2H), 0.28-0.41 (m, 4H). MS (ES⁺): m/z = 486.23 [MH⁺]. UPLC: t_(R) = 1.00min (TOF: polar_2 min). 176 (7R)-8-cyclohexyl-2-[(7-fluoro- ¹H NMR (400MHz, CD₃OD): δ 7.99 (br. s., 1H), 1H-indazol-5-yl)amino]-7- 7.75-7.84(m, 2H), 7.50 (d, J = 12.6 Hz, 1H), 7.40 methyl-5-(1-methyl-2-oxo-1,2-(s, 1H), 6.56 (br. s., 1H), 6.29 (d, J = 6.8 Hz, 1H),dihydropyridin-4-yl)-7,8- 4.46 (d, J = 6.1 Hz, 2H), 3.62 (s, 3H), 2.16(d, J = dihydropteridin-6(5H)-one 9.6 Hz, 1H), 1.92 (d, J = 11.1 Hz,2H), 1.68-1.84 (m, 3H), 1.60 (br. s., 1H), 1.38-1.54 (m, 5H), 1.29 (br.s., 1H). MS (ES⁺): m/z = 503.72 [MH⁺]. UPLC: t_(R) = 0.75 min (TOF:polar_2 min). 177 methyl 4-[(7R)-8-cyclohexyl-2- ¹H NMR (CDCl₃, 300 MHz)δ 1.18-1.22 (m, 1H), (1H-indazol-5-ylamino)-7- 1.43-1.52 (m, 6H),1.65-1.80 (m, 3H), 1.90-1.98 methyl-6-oxo-7,8- (m, 2H), 2.19-2.25 (m,1H), 3.89 (s, 3H), 4.40-4.47 dihydropteridin-5(6H)- (m, 2H), 6.99 (s,1H), 7.35 (s, 1H), 7.40-7.43 (m, yl]thiophene-2-carboxylate 2H), 7.54(d, J = 1.8 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 8.02 (br s, 1H), 8.16 (s,1H), 10.02 (br s, 1H). MS(ES⁺): m/z = 518.35 [MH⁺]. HPLC: t_(R) = 2.54(ZQ3, Polar_5 min). 178 2-(1H-indazol-5-ylamino)-7- ¹HNMR (300 MHz,DMSO-d₆): δ 1.47 (d, J = 6.6 methyl-5,8-diphenyl-7,8- Hz, 3H), 4.77-4.99(m, 1H), 7.05 (s, 1H), 7.20- dihydropteridin-6(5H)-one 7.31 (m, 2H),7.43-7.63 (m, 10H), 7.81 (s, 2H), 9.15 (s, 1H). MS(ES⁺): m/z = 448.00[MH⁺]. HPLC: t_(R) = 2.51 (ZQ3, Polar_5 min). 1797-methyl-2-[(2-oxo-2,3- ¹HNMR (300 MHz, CDCl₃) δ 1.63 (d, J = 6.6 Hz,dihydro-1H-indol-5-yl)amino]- 3H), 3.33 (s, 2H), 4.68-4.75 (m, 1H), 6.66(d, J = 5,8-diphenyl-7,8- 8.4 Hz, 1H), 6.75 (s, 1H), 6.93 (d, J = 8.1Hz, 1H) dihydropteridin-6(5H)-one and 7.31-7.59 (m, 12H). MS(ES⁺): m/z =463.07 [MH⁺]. HPLC: t_(R) = 2.39 (ZQ3, Polar_5 min). 1803-[(7R)-2-[(7-fluoro-1H- ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.46 (d, J = 6.9indazol-5-yl)amino]-8-(4- Hz, 3H), 4.77 (q, J = 6.9, 13.8 Hz, 1H), 7.13(s, fluorophenyl)-7-methyl-6-oxo- 1H), 7.25 (d, J = 13.2 Hz, 1H), 7.44(t, J = 8.7 Hz, 7,8-dihydropteridin-5(6H)- 2H), 7.57-7.60 (m, 2H), 7.74(s, 1H), 7.81 (d, J = yl]benzonitrile 5.4 Hz, 2H), 7.98-8.04 (m, 2H),9.30 (s, 1H). MS(ES⁺): m/z = 509.62[MH⁺]. HPLC: t_(R) = 0.93 min(analytical_2 min, UPLC). 181 3-[(7R)-2-[(7-fluoro-1H- ¹H NMR (DMSO-d₆,300 MHz) δ: 1.46 (d, J = 6.9 indazol-5-yl)amino]-8-(3- Hz, 3H), 3.87 (s,3H), 4.71 (q, 1H), 7.08 (s, 1H), methoxyphenyl)-7-methyl-6- 7.15 (d, J =9 Hz, 2H), 7.23 (d, J = 13.5 Hz, 1H), oxo-7,8-dihydropteridin-5(6H)-7.44 (d, J = 8.7 Hz, 1H), 7.57 (s, 1H), 7.68 (s, 1H), yl]benzonitrile7.80-7.82 (m, 2H), 7.99-8.03 (m, 2H), 9.24 (s, 1H). MS(ES⁺): m/z =521.65[MH⁺]. HPLC: t_(R) = 0.92 min (analytical_2 min, UPLC). 1823-[(7R)-2-[(7-fluoro-1H- ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.46 (d, J = 6.9indazol-5-yl)amino]-8-(4- Hz, 3H), 3.87 (s,3H), 4.71 (q, 1H), 7.15 (d, J= 9 methoxyphenyl)-7-methyl-6- Hz, 2H), 7.20-7.25 (m, 1H), 7.44 (d, J =8.7 Hz, oxo-7,8-dihydropteridin-5(6H)- 2H), 7.57 (s, 1H), 7.66-7.70 (m,1H), 7.80-7.82 (m, yl]benzonitrile 2H), 7.99-8.02 (m, 2H), 9.24 (br s,1H). MS(ES⁺): m/z = 521.76[MH⁺]. HPLC: t_(R) = 2.61 min (ZQ3, Polar_5min). 183 3-[(7R)-2-[(7-fluoro-1H- ¹H NMR (CDCl₃, 300 MHz) δ: 1.62 (d, J= 6.9 Hz, indazol-5-yl)amino]-8-(3- 3H), 4.74 (q, J = 16.8, 6.9 Hz, 1H),7.09-7.22 (m, fluorophenyl)-7-methyl-6-oxo- 4H), 7.31 (s, 1H), 7.42-7.62(m, 3H), 7.68-7.72 (m, 7,8-dihydropteridin-5(6H)- 2H), 7.78-7.80 (m,1H), 7.89 (s, 1H), 10.32 (br s, yl]benzonitrile 1H). MS(ES⁺): m/z =509.76 [MH⁺]. HPLC: t_(R) = 2.78 min (ZQ3, Polar_5 min).

Examples 95-177 were prepared according to procedures similar to thepreparation of Example 18, using corresponding starting materials andintermediates. For example, for the synthesis of example 100,(3-cyanophenyl)boronic acid was used in the step d of the synthesis,4-fluoro-1H-indazol-5-amine was used in the step e of the synthesis.

Example 178 was prepared by the following procedures:

Step a: Synthesis of ethyl 2-{[(trifluoromethyl)sulfonyl]oxy}propanoate

To a stirred solution of trifluoromethanesulfonic anhydride (30 mL, 170mmol) in anhydrous dichloromethane (50 mL) was added drop-wise asolution of 2-hydroxypropanoic acid ethyl ester (20 g, 170 mmol) andpyridine (14 mL) in dichloromethane (50 mL) at 0° C. (Ice bath) over aperiod of 1 h under nitrogen. The ice bath was then removed and thereaction mixture was stirred for additional 2 h. The inorganic salt wasthen filtered off and the organic solution was washed with water, driedover sodium sulfate, and evaporated to give desired product as pinkcolored oil (37.4 g, 88%) which was used as such for the next step.¹HNMR (300 MHz, CDCl₃): δ 1.38 (t, J=4.8 Hz, 3H), 1.77 (d, J=4.8 Hz,3H), 4.32-4.37 (m, 2H) and 5.28 (q, J=6.9 Hz, 1H).

Step b: Synthesis of ethyl N-phenylalaninate

To a stirred solution of aniline (4.55 mL, 50 mmol) and triethylamine (7mL, 50 mmol) in anhydrous dichloromethane (120 mL) was added a solutionof ethyl 2-{[(trifluoromethyl)sulfonyl]oxy}propanoate (12.5 g, 50 mmol)in dichloromethane (60 mL) at 0° C. (Ice bath) over a period of 30minutes under nitrogen. The ice bath was then removed and the reactionmixture was stirred at 35° C. for 2 h. The reaction mixture was cooledto rt, washed with water, dried over sodium sulfate, and evaporated togive desired product as oil (8.9 g, 92%) which was used as such for thenext step. ¹HNMR (300 MHz, CDCl₃): δ 1.19-1.67 (m, 6H), 4.17-4.38 (m,3H), 6.65-6.80 (m, 3H), 7.20-7.35 (m, 2H).

Step c: Synthesis of ethylN-(2-chloro-5-nitropyrimidin-4-yl)-N-phenylalaninate

A solution of ethyl N-phenylalaninate (9.65 g, 50 mmol) and2,4-dichloro-5-nitropyrimidine (9.7 g, 50 mmol) in anhydrousdichloromethane (100 mL) was stirred for 5 minutes at rt under nitrogen.The solution was then cooled to 0° C. (Ice bath) followed by addition ofimidazole (3.41 g, 50 mmol). The resulting reaction mixture was allowedto warm up to rt in 30 min and further heated at 50° C. for 2 h. Thereaction was then cooled to rt, washed with water, dried over sodiumsulfate and evaporated to give a crude residue, which was purified bysilica gel flash chromatography (eluent: ethyl acetate-hexane mixture(5:95)) to afford desired product (22%). ¹HNMR (300 MHz, CDCl₃): δ 1.29(t, J=7.2 Hz, 3H), 1.63 (d, J=7.5 Hz, 3H), 4.18-4.27 (m, 2H), 4.90 (q,J=7.2 Hz, 1H), 7.19 (d, J=6.9 Hz, 2H), 7.26-7.39 (m, 3H) and 8.52 (s,1H).

Step d: 2-chloro-7-methyl-8-phenyl-7,8-dihydropteridin-6(5H)-one

To a stirred solution of ethylN-(2-chloro-5-nitropyrimidin-4-yl)-N-phenylalaninate (1.6 g, 4.56 mmol)in glacial acetic acid (35 mL) was added iron powder (1.6 g, 28.57mmol). The resulting mixture was heated at 70° C. for 2 h. The insolublematerial was then filtered off celite to give a clear solution. The bulkof solvent was evaporated to give a crude residue, which was purified bysilica gel flash chromatography (eluent: 2% methanol in dichloromethane)to afford desired product (75%). ¹HNMR (300 MHz, DMSOd₆): δ 1.29 (d,J=6.6 Hz, 3H), 4.58-4.60 (m, 1H), 7.36-7.50 (m, 5H), 7.70 (s, 1H) and10.94 (s, 1H).

Step e: Synthesis of2-chloro-7-methyl-5,8-diphenyl-7,8-dihydropteridin-6(5H)-one

To a stirred solution of2-chloro-7-methyl-8-phenyl-7,8-dihydropteridin-6(5H)-one (1.59 g, 5.78mmol) in dichloromethane (75 mL) was added triethylamine (8.07 ml, 57.8mmol), cupric acetate (2.09 g, 11.56 mmol) and phenylboronic acid (1.41g, 11.56 mmol) followed by 4 Å molecular sieves (2 g). The resultingmixture was stirred for 48 h at rt with an air balloon on the top. Thereaction mixture was then filtered over celite to give a clear solution.The solution was washed with aqueous saturated sodium bicarbonate (50mL×2), dried over anhydrous sodium sulfate and evaporated to give acrude material, which was then purified by silica gel columnchromatography (eluent: 2% methanol in dichloromethane) to give thedesired product (750 mg, 37%). ¹HNMR (300 MHz, CDCl₃): δ 1.65 (d, J=6.9Hz, 3H), 4.82 (q, J=6.9 Hz, 1H) and 7.36-7.65 (m, 11H).

Step f: Synthesis of2-(1H-indazol-5-ylamino)-7-methyl-5,8-diphenyl-7,8-dihydropteridin-6(5H)-one

To a mixture of2-chloro-7-methyl-5,8-diphenyl-7,8-dihydropteridin-6(5H)-one (175 mg,0.5 mmol), 5-aminoindazole (99 mg, 0.75 mmol), in trifluoroethanol (2mL) in a microwave reactor vial was added trifluoroacetic acid (171 mg).The vial was then sealed and heated in a microwave reactor at 125° C.for 30 minutes. The reaction mixture was then diluted with ethyl acetate(25 mL) and washed with aqueous saturated aq. sodium bicarbonate. Theorganic layer was dried (Na₂SO₄) and evaporated to give a crudematerial, which was then purified by silica gel column chromatography(eluent: 2% methanol in dichloromethane) to give the desired product(40%).

Examples 179-183 were prepared according to procedures similar to thepreparation of Example 178, using corresponding starting materials andintermediates. For example, for the synthesis of example 180, ethyl(2S)-2-hydroxypropanoate was used in the step a of the synthesis,4-fluoroaniline was used in the step b of the synthesis,(3-cyanophenyl)boronic acid was used in the step e of the synthesis and7-fluoro-1H-indazol-5-amine was used in the step f of the synthesis.

Ex. # Chemical Name Analytical data 1843-[(7R)-2-(1H-indazol-5-ylamino)- ¹H NMR (CDCl₃, 300 MHz) δ 1.50 (d, J =6.9 7-methyl-6-oxo-8-(tetrahydro-2H- Hz, 3H), 1.75-1.79 (m, 1H),1.92-2.00 (m, 1H), pyran-4-yl)-7,8-dihydropteridin- 2.12-2.17 (m, 2H),3.51-3.61(m, 2H), 4.12-4.16 5(6H)-yl]benzonitrile (m, 2H), 4.45 (q, J =6.9 Hz, 1H), 4.56-4.62 (m, 1H), 6.96 (s, 1H), 7.18(s, 1H), 7.37-7.45 (m,2H), 7.51-7.54 (m, 1H), 7.60-7.67 (m, 2H), 7.73-7.76 (m, 1H), 8.01(s,1H), 8.09 (s, 1H), 10.09 (br s, 1H). MS(ES⁺): m/z = 481.13 (100) [MH⁺].HPLC: t_(R) = 2.03 (ZQ3, Polar_5 min). [α]_(D) = −47.5(c = 0.8 inCH₂Cl₂). 185 3-[(7R)-2-[(4-fluoro-1H-indazol-5- ¹H NMR (CDCl₃, 300 MHz)δ 1.49 (d, J = 6.6 yl)amino]-7-methyl-6-oxo-8- Hz, 3H), 1.70-1.74 (m,1H), 1.80-1.92 (m, 1H), (tetrahydro-2H-pyran-4-yl)-7,8- 2.04-2.14 (m,2H), 3.39-3.56 (m, 2H), 4.05-4.12 dihydropteridin-5(6H)- (m, 2H),4.40-4.57 (m, 2H), 6.88 (s, 1H), 7.14 yl]benzonitrile (1H), 7.24-7.26(m, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.64 (t, J = 7.5 Hz,1H), 7.72- 7.76 (m, 1H), 7.98-8.04 (m, 1H), 8.12 (s, 1H). MS(ES⁺): m/z =498.72 [MH⁺]. HPLC: t_(R) = 2.14 (ZQ3, Polar_5 min). 1863-[(7R)-2-[(7-fluoro-1H-indazol-5- ¹H NMR (CDCl₃, 400 MHz): δ 1.44 (d, J= 6.8 yl)amino]-7-methyl-6-oxo-8- Hz, 3 H), 1.71 (m, 1 H), 1.89 (m, 1H), 2.05- (tetrahydro-2H-pyran-4-yl)-7,8- 2.10 (m, 2 H), 3.48-3.56 (m, 2H), 4.06-4.11 (m, dihydropteridin-5(6H)- 2 H), 4.40 (q, J = 6.8 Hz, 1H), 4.55 (m, 1 H), yl]benzonitrile 7.04 (s, 1 H), 7.13 (s, 1 H), 7.42(dd, J = 1.6, 12.4 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.53 (m, 1 H),7.58 (t, J = 6.4 Hz, 1 H), 7.59 (s, 1 H), 7.68 (dt, J = 1.6, 8.0 Hz, 1H), 7.96 (d, J = 3.6 Hz, 1 H), 10.52 (s, br, 1 H). MS (ES⁺): m/z =499.39 [MH⁺]. HPLC: t_(R) = 0.75 min (TOF, polar_2 min). 187(7R)-5-(3,4-dimethoxyphenyl)-2- 1H NMR (400 MHz, CD₃OD): δ 1.50 (d, J =6.57 [(3-fluoro-1H-indazol-5-yl)amino]- Hz, 3H), 1.78 (d, J = 12.63 Hz,1H), 1.92-2.30 7-methyl-8-(tetrahydro-2H-pyran- (m, 3H), 3.50-3.67 (m,2H), 3.84 (s, 3H), 3.91 4-yl)-7,8-dihydropteridin-6(5H)- (s, 3H),4.03-4.16 (m, 2H), 4.50 (q, J = 6.74 Hz, one 1H), 4.64-4.76 (m, 1H),6.77-6.92 (m, 2H), 7.05-7.17 (m, 2H), 7.36 (dd, J = 9.22, 1.89 Hz, 1H),7.47 (dd, J = 9.1, 2.02 Hz, 1H), 8.08 (d, J = 1.2 Hz, 1H). MS(ES⁺): m/z= 534.48[MH⁺]. HPLC: t_(R) = 0.75 (analytical_2 min, UPLC). 188(7R)-5-(3,4-dimethoxyphenyl)-2- ¹H NMR (400 MHz, CD₃OD): δ 1.50 (d, J =6.5 [(7-fluoro-1H-indazol-5-yl)amino]- Hz, 3H), 1.77 (d, J = 11.3 Hz,1H), 2.08 (br. s., 7-methyl-8-(tetrahydro-2H-pyran- 2H), 2.26 (d, J =8.5 Hz, 1H), 3.47-3.65 (m, 4-yl)-7,8-dihydropteridin-6(5H)- 2H), 3.83(s, 3H), 3.90 (s, 3H), 4.04-4.15 (m, one 2H), 4.49 (d, J = 6.0 Hz, 1H),4.59 (br. s., 1H), 6.87 (br. s., 2H), 7.12 (d, J = 8.3 Hz, 2H), 7.46 (d,J = 12.8 Hz, 1H), 7.79 (br. s., 1H), 8.03 (br. s., 1H). MS(ES⁺): m/z =534.45[MH⁺]. HPLC: t_(R) = 0.72 min (analytical_2 min, UPLC). 189(7R)-2-[(7-fluoro-1H-indazol-5- ¹H NMR (400 MHz, CD₃OD): δ 1.50 (d, J =6.5 yl)amino]-5-(3-fluorophenyl)-7- Hz, 3H), 1.77 (d, J = 11.3 Hz, 1H),2.08 (br. s., methyl-8-(tetrahydro-2H-pyran-4- 2H), 2.26 (d, J = 8.3 Hz,1H), 3.45-3.62 (m, yl)-7,8-dihydropteridin-6(5H)-one 2H), 4.00-4.16 (m,2H), 4.50 (d, J = 6.5 Hz, 1H), 4.59 (br. s., 1H), 7.14 (d, J = 5.5 Hz,2H), 7.28 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 13.1 Hz, 1H), 7.55-7.66 (m,1H), 7.79 (br. s., 1H), 8.04 (br. s., 1H). MS(ES⁺): m/z = 492.36[MH⁺].HPLC: t_(R) = 0.76 min (analytical_2 min, UPLC). 1905-[(7R)-2-[(7-fluoro-1H-indazol-5- ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, J= 3.3 yl)amino]-7-methyl-6-oxo-8- Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H),7.66 (d, J = (tetrahydro-2H-pyran-4-yl)-7,8- 2.0 Hz, 1H), 7.53-7.60 (m,1H), 7.46 (d, J = dihydropteridin-5(6H)-yl]-2- 13.1 Hz, 1H), 7.36 (d, J= 9.1 Hz, 1H), 7.10 (s, methoxybenzonitrile 1H), 4.60 (br. s., 1H), 4.50(q, J = 6.8 Hz, 1H), 4.05-4.13 (m, 2H), 4.03 (s, 3H), 3.49-3.62 (m, 2H),2.25 (dd, J = 4.7, 12.3 Hz, 1H), 2.02-2.13 (m, 2H), 1.77 (d, J = 12.9Hz, 1H), 1.49 (d, J = 6.6 Hz, 3H). MS (ES⁺): m/z = 529.21 [MH⁺]. UPLC:t_(R) = 0.65 min (TOF: polar_2 min). 191 (7R)-2-[(7-fluoro-1H-indazol-5-¹H NMR (400 MHz, CD₃OD): δ 1.52 (d, J = 6.82yl)amino]-7-methyl-5-(pyridin-3- Hz, 4H), 1.74-1.86 (m, 1H), 2.03-2.13(m, 2H), yl)-8-(tetrahydro-2H-pyran-4-yl)- 3.49-3.64 (m, 4H), 4.09 (d, J= 13.8 Hz, 2H), 7,8-dihydropteridin-6(5H)-one 7.11 (s, 1H), 7.48 (d, J =13.1 Hz, 1H), 7.65 (dd, J = 8.7, 4.9 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H),7.84-7.91 (m, 1H), 8.02 (br. s., 1H), 8.50- 8.50 (m, 1H), 8.67 (dd, J =4.9, 1.39 Hz, 1H). MS(ES⁺): m/z = 475.32 [MH⁺]. HPLC: t_(R) = 0.59 min(analytical_2 min, UPLC). 192 (7R)-2-[(7-fluoro-1H-indazol-5- ¹H NMR(400 MHz, CD₃OD): δ 1.50 (d, J = 6.8 yl)amino]-5-(6-methoxypyridin-3-Hz, 3H), 1.77 (d, J = 11.3 Hz, 1H), 2.00-2.13yl)-7-methyl-8-(tetrahydro-2H- (m, 2H), 2.19-2.33 (m, 1H), 3.46-3.64 (m,2H), pyran-4-yl)-7,8-dihydropteridin- 3.98 (s, 3H), 4.03-4.13 (m, 2H),4.51 (q, J = 6(5H)-one 6.40 Hz, 1H), 4.59 (br. s., 1H), 6.98 (d, J = 8.5Hz, 1H), 7.48 (d, J = 13.14 Hz, 1H), 7.61(d, J = 7.8 Hz, 1H), 7.80 (br.s., 1H), 7.99-8.14 (m, 2H). MS(ES⁺): m/z = 505.57[MH⁺]. HPLC: t_(R) =0.71 min (analytical_2 min, UPLC). 193 (7R)-2-[(7-fluoro-1H-indazol-5-1H NMR (400 MHz, CDCl₃): δ 1.50 (d, J = 6.5 yl)amino]-7-methyl-5-[6-(4-Hz, 3H), 1.79 (d, J = 12.13 Hz, 2H), 2.09-2.20methylpiperazin-1-yl)pyridin-3-yl]- (m, 2H), 2.45 (br. s., 3H), 2.65(br. s., 4H), 3.59 8-(tetrahydro-2H-pyran-4-yl)-7,8- (ddd, J = 11.75,9.85, 5.68 Hz, 2H), 3.73 (br. s., dihydropteridin-6(5H)-one 4H),4.06-4.21 (m, 2H), 4.46 (q, J = 6.82 Hz, 1H), 4.56-4.71 (m, 1H), 6.76(d, J = 9.09 Hz, 1H), 7.04 (br. s., 1H), 7.31 (s, 1H), 7.35 (dd, J =8.72, 2.15 Hz, 1H), 7.49 (dd, J = 12.63, 1.52 Hz, 1H), 7.66 (d, J = 1.52Hz, 1H), 7.99-8.09 (m, 2H). MS(ES⁺): m/z = 573.74 [MH⁺]. HPLC: t_(R) =0.50 (analytical_2 min, UPLC). 194 3-[(7R)-2-[(3,5-difluoro-4- ¹H NMR(400 MHz, CD₃OD): δ 7.84-7.90 (m, hydroxyphenyl)amino]-7-methyl- 1H),7.70-7.81 (m, 2H), 7.64 (d, J = 8.1 Hz, 6-oxo-8-(tetrahydro-2H-pyran-4-1H), 7.20-7.33 (m, J = 10.9 Hz, 2H), 7.08 (s,yl)-7,8-dihydropteridin-5(6H)- 1H), 4.67 (tt, J = 3.8, 12.1 Hz, 1H),4.52 (q, J = yl]benzonitrile 6.8 Hz, 1H), 4.04-4.15 (m, 2H), 3.60 (t, J= 11.7 Hz, 2H), 2.08-2.22 (m, 2H), 1.92-2.05 (m, J = 3.9, 11.7 Hz, 1H),1.78 (d, J = 11.1 Hz, 1H), 1.50 (d, J = 6.6 Hz, 3H). 1952-Ethoxy-5-[(7R)-2-[(7-fluoro-1H- ¹H NMR (400 MHz, CD₃OD): δ 8.02 (br.s., 1H), indazol-5-yl)amino]-7-methyl-6- 7.79 (s, 1H), 7.64 (d, J = 2.3Hz, 1H), 7.53 (d, J = oxo-8-(tetrahydro-2H-pyran-4- 8.8 Hz, 1H), 7.46(d, J = 13.1 Hz, 1H), 7.33 yl)-7,8-dihydropteridin-5(6H)- (d, J = 9.1Hz, 1H), 7.10 (s, 1H), 4.59 (t, J = yl]benzonitrile 11.5 Hz, 1H), 4.50(q, J = 6.8 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H), 4.04-4.12 (m, 2H),3.49-3.63 (m, 2H), 2.17-2.31 (m, 1H), 2.00-2.13 (m, 2H), 1.76 (d, J =12.1 Hz, 1H), 1.45-1.53 (m, 6H). MS (ES⁺): m/z = 543.22 [MH⁺]. UPLC:t_(R) = 0.71 min (TOF: polar_2 min). 1965-[(7R)-2-[(7-fluoro-1H-indazol-5- ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, J= 2.8 yl)amino]-7-methyl-6-oxo-8- Hz, 1H), 7.79 (s, 1H), 7.64 (d, J =2.5 Hz, 1H), (tetrahydro-2H-pyran-4-yl)-7,8- 7.52 (d, J = 8.8 Hz, 1H),7.47 (d, J = 12.6 Hz, dihydropteridin-5(6H)-yl]-2- 1H), 7.36 (d, J = 9.1Hz, 1H), 7.11 (s, 1H), 4.59 (propan-2-yloxy)benzonitrile (d, J = 7.1 Hz,1H), 4.50 (q, J = 6.7 Hz, 1H), 4.04-4.13 (m, 2H), 3.46-3.62 (m, 3H),2.25 (dd, J = 4.5, 12.1 Hz, 1H), 2.08 (br. s., 2H), 1.77 (d, J = 12.6Hz, 1H), 1.49 (d, J = 6.6 Hz, 3H), 1.44 (d, J = 6.1 Hz, 6H). MS (ES⁺):m/z = 557.23 [MH⁺]. UPLC: t_(R) = 0.76 min (TOF: polar_2 min). 1972-Methoxy-5-[(7R)-7-methyl-6- ¹H NMR (400 MHz, CD₃OD): δ 7.80 (d, J =1.8 oxo-2-[(2-oxo-2,3-dihydro-1,3- Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H),7.56 (dd, J = benzoxazol-6-yl)amino]-8- 1.9, 9.0 Hz, 1H), 7.35 (d, J =9.1 Hz, 1H), 7.19 (tetrahydro-2H-pyran-4-yl)-7,8- (dd, J = 2.0, 8.3 Hz,1H), 7.09 (s, 1H), 6.97 (d, dihydropteridin-5(6H)- J = 8.6 Hz, 1H),4.55-4.65 (m, 1H), 4.49 (q, J = yl]benzonitrile. 6.7 Hz, 1H), 4.09 (d, J= 11.4 Hz, 2H), 4.03 (s, 3H), 3.58 (t, J = 11.7 Hz, 2H), 1.94-2.27 (m,3H), 1.76 (d, J = 12.4 Hz, 1H), 1.48 (d, J = 6.8 Hz, 3H). MS (ES⁺): m/z= 528.19 [MH⁺]. UPLC: t_(R) = 0.62 min (TOF: polar_2 min). 1982-Ethoxy-5-[(7R)-7-methyl-6-oxo- ¹H NMR (400 MHz, CD₃OD): δ 7.81 (d, J =2.0 2-[(2-oxo-2,3-dihydro-1,3- Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.53(dd, J = benzoxazol-6-yl)amino]-8- 2.0, 8.8 Hz, 1H), 7.33 (d, J = 9.1Hz, 1H), 7.19 (tetrahydro-2H-pyran-4-yl)-7,8- (dd, J = 2.0, 8.3 Hz, 1H),7.09 (s, 1H), 6.97 (d, dihydropteridin-5(6H)- J = 8.3 Hz, 1H), 4.61 (tt,J = 3.6, 11.9 Hz, 1H), yl]benzonitrile. 4.50 (q, J = 6.8 Hz, 1H), 4.28(q, J = 6.9 Hz, 2H), 4.06-4.11 (m, 2H), 3.52-3.64 (m, 2H), 2.07-2.26 (m,2H), 1.94-2.06 (m, 2H), 1.73-1.80 (m, 1H), 1.46-1.51 (m, 5H). MS (ES⁺):m/z = 542.21 [MH⁺]. UPLC: t_(R) = 0.68 min (TOF: polar_2 min). 1995-[(7R)-7-methyl-6-oxo-2-[(2-oxo- ¹H NMR (400 MHz, CD₃OD): δ 7.80 (d, J= 1.8 2,3-dihydro-1,3-benzoxazol-6- Hz, 1H), 7.63 (s, 1H), 7.51 (d, J =7.6 Hz, 1H), yl)amino]-8-(tetrahydro-2H- 7.35 (d, J = 8.8 Hz, 1H), 7.19(dd, J = 1.9, 8.7 pyran-4-yl)-7,8-dihydropteridin- Hz, 1H), 7.10 (s,1H), 6.96-7.00 (m, 1H), 4.60 5(6H)-yl]-2-(propan-2- (d, J = 11.6 Hz,1H), 4.50 (q, J = 6.9 Hz, 1H), yloxy)benzonitrile 4.09 (d, J = 10.9 Hz,2H), 3.54-3.64 (m, 2H), 2.07-2.22 (m, 2H), 2.01 (dd, J = 4.4, 11.7 Hz,1H), 1.77 (d, J = 10.4 Hz, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.44 (d, J =6.1 Hz, 7H). MS (ES⁺): m/z = 556.23 [MH⁺]. UPLC: t_(R) = 0.73 min (TOF:polar_2 min). 200 2-methoxy-5-[(7R)-7-methyl-6- ¹H NMR (400 MHz, CD₃OD):δ 8.62 (d, J = 2.3 oxo-2-(1H-pyrazolo[3,4-b]pyridin- Hz, 1H), 8.53 (d, J= 2.3 Hz, 1H), 8.04 (s, 1H), 5-ylamino)-8-(tetrahydro-2H- 7.65 (d, J =2.0 Hz, 1H), 7.53 (dd, J = 2.0, 9.1 pyran-4-yl)-7,8-dihydropteridin- Hz,1H), 7.33 (d, J = 9.1 Hz, 1H), 7.11 (s, 1H), 5(6H)-yl]benzonitrile4.45-4.57 (m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.99-4.10 (m, 2H),3.43-3.59 (m, 2H), 2.23 (dq, J = 4.4, 12.2 Hz, 1H), 1.99-2.08 (m, 2H),1.74 (d, J = 12.1 Hz, 1H), 1.52 (s, 6H). MS (ES⁺): m/z = 512.21 [MH⁺].UPLC: t_(R) = 0.58 min (TOF: polar_2 min). 2012-Ethoxy-5-[(7R)-7-methyl-6-oxo- ¹H NMR (400 MHz, CD₃OD): δ 8.62 (d, J =2.3 2-(1H-pyrazolo[3,4-b]pyridin-5- Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H),8.04 (s, 1H), ylamino)-8-(tetrahydro-2H-pyran- 7.65 (d, J = 2.0 Hz, 1H),7.53 (dd, J = 2.0, 9.1 4-yl)-7,8-dihydropteridin-5(6H)- Hz, 1H), 7.33(d, J = 9.1 Hz, 1H), 7.11 (s, 1H), yl]benzonitrile. 4.45-4.57 (m, 2H),4.27 (q, J = 7.1 Hz, 2H), 3.99-4.10 (m, 2H), 3.43-3.59 (m, 2H), 2.23(dq, J = 4.4, 12.2 Hz, 1H), 1.99-2.08 (m, 2H), 1.74 (d, J = 12.1 Hz,1H), 1.52 (s, 6H). MS (ES⁺): m/z = 526.22 [MH⁺]. UPLC: t_(R) = 0.64 min(TOF: polar_2 min). 202 5-[(7R)-7-methyl-6-oxo-2-(1H- ¹H NMR (400 MHz,CD₃OD): δ 8.63 (d, J = 2.0 pyrazolo[3,4-b]pyridin-5- Hz, 1H), 8.53 (d, J= 2.3 Hz, 1H), 8.04 (s, 1H), ylamino)-8-(tetrahydro-2H- 7.64 (s, 1H),7.52 (d, J = 7.8 Hz, 1H), 7.36 (d, J = pyran-4-yl)-7,8-dihydropteridin-9.1 Hz, 1H), 7.12 (s, 1H), 4.44-4.60 (m, 2H), 5(6H)-yl]-2-(propan-2-4.00-4.13 (m, 2H), 3.40-3.60 (m, 3H), 2.17-2.30 yloxy)benzonitrile (m,1H), 2.02-2.08 (m, 2H), 1.75 (d, J = 12.6 Hz, 1H), 1.49 (d, J = 6.6 Hz,3H), 1.44 (d, J = 6.1 Hz, 6H). MS (ES⁺): m/z = 540.24 [MH⁺]. UPLC: t_(R)= 0.69 min (TOF: polar_2 min). 203 5-[(7R)-2-[(4-fluoro-2-oxo-2,3- ¹HNMR (400 MHz, CD₃OD): δ 7.65 (br. s., 1H), dihydro-1,3-benzoxazol-6-7.56 (d, J = 7.3 Hz, 1H), 7.51 (s, 1H), 7.31-7.39yl)amino]-7-methyl-6-oxo-8- (m, 2H), 7.13 (s, 1H), 4.65 (t, J = 12.0 Hz,1H), (tetrahydro-2H-pyran-4-yl)-7,8- 4.51 (q, J = 6.7 Hz, 1H), 4.10 (d,J = 11.1 Hz, dihydropteridin-5(6H)-yl]-2- 2H), 4.03 (s, 3H), 3.60 (t, J= 11.9 Hz, 2H), methoxybenzonitrile. 2.09-2.25 (m, 2H), 1.96-2.08 (m, J= 4.5 Hz, 1H), 1.78 (d, J = 11.9 Hz, 1H), 1.49 (d, J = 6.6 Hz, 3H). MS(ES⁺): m/z = 546.19 [MH⁺]. UPLC: t_(R) = 0.70 min (TOF: polar_2 min).204 2-Ethoxy-5-[(7R)-2-[(4-fluoro-2- ¹H NMR (400 MHz, CD₃OD): δ 7.64 (s,1H), oxo-2,3-dihydro-1,3-benzoxazol- 7.49-7.55 (m, 2H), 7.30-7.38 (m,2H), 7.13 (s, 6-yl)amino]-7-methyl-6-oxo-8- 1H), 4.66 (s, 1H), 4.51 (d,J = 6.8 Hz, 1H), 4.10 (tetrahydro-2H-pyran-4-yl)-7,8- (d, J = 11.9 Hz,2H), 3.61 (t, J = 11.7 Hz, 2H), dihydropteridin-5(6H)- 2.09-2.23 (m,2H), 1.96-2.07 (m, 1H), 1.78 (d, J = yl]benzonitrile. 13.1 Hz, 1H),1.45-1.53 (m, 8H). MS (ES⁺): m/z = 560.21 [MH⁺]. UPLC: t_(R) = 0.77 min(TOF: polar_2 min) 205 5-[(7R)-2-[(4-fluoro-2-oxo-2,3- ¹H NMR (400 MHz,CD₃OD): δ 7.60-7.64 (m, dihydro-1,3-benzoxazol-6- 1H), 7.48-7.54 (m,2H), 7.31-7.38 (m, 2H), yl)amino]-7-methyl-6-oxo-8- 7.12-7.15 (m, 1H),4.54-4.72 (m, 1H), 4.40-4.54 (tetrahydro-2H-pyran-4-yl)-7,8- (m, 1H),4.06-4.15 (m, 2H), 3.55-3.65 (m, 3H), dihydropteridin-5(6H)-yl]-2-2.10-2.18 (m, 2H), 1.96-2.06 (m, 1H), 1.74-1.81(propan-2-yloxy)benzonitrile. (m, 1H), 1.47-1.50 (m, 3H), 1.43-1.45 (m,6H). MS (ES⁺): m/z = 574.22 [MH⁺]. UPLC: t_(R) = 0.81 min (TOF: polar_2min). 206 5-[(7R)-2-[(7-fluoro-1H-indazol-5- ¹H NMR (CDCl₃, 400 MHz): δ1.48 (d, J = 6.8 yl)amino]-7-methyl-6-oxo-8- Hz, 3 H), 1.76 (m, 1 H),1.96 (dq, J = 3.6, 11.60 (tetrahydro-2H-pyran-4-yl)-7,8- Hz, 1 H),2.07-2.17 (m, 2 H), 2.38 (s, 3 H), 2.65 dihydropteridin-5(6H)-yl]-2-(4-(t, J = 4.8 Hz, 4 H), 3.35 (t, J = 4.8 Hz, 4 H),methylpiperazin-1-yl)benzonitrile 3.56 (q, J = 10.4 Hz, 2 H), 4.11-4.14(m, 2 H), 4.43 (q, J = 6.8 Hz, 1 H), 4.59 (m, 1 H), 6.94 (s, 1 H), 7.09(d, J = 8.8 Hz, 1 H), 7.24-7.25 (m, 2 H), 7.32 (dd, J = 2.0, 8.8 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1 H), 7.47 (d, J = 12.8 Hz, 1 H), 7.65 (s, 1H), 8.01 (d, J = 2.8 Hz, 1 H). MS (ES⁺): m/z = 597.46 [MH⁺]. HPLC: t_(R)= 0.54 min (TOF, polar_2 min).

Examples 184-206 were prepared according to procedures similar to thepreparation of Example 18, using corresponding starting materials andintermediates. For example, for the synthesis of example 186,tetrahydro-4H-pyran-4-one and D-Alanine methyl ester hydrochloride wereused in the step a of the synthesis, (3-cyanophenyl)boronic acid wasused in the step d of the synthesis and 7-fluoro-1H-indazol-5-amine wasused in the step e of the synthesis.

Ex. # Chemical Name Analytical data 207 3-[(7R)-8-(4,4- ¹H NMR (CDCl₃,300 MHz) δ 0.93-0.95 (m, 6H), dimethylcyclohexyl)-2-(1H- 1.39-1.46 (m,5H), 1.51-1.61 (m, 4H), 1.82-1.84 indazol-5-ylamino)-7-methyl-6- (m,1H), 1.97-1.99 (m, 1 H), 4.35-4.47 (m, 2H),oxo-7,8-dihydropteridin-5(6H)- 7.03 (s, 1H), 7.29-7.32 (m, 1H),7.37-7.41 (m, yl]benzonitrile 1H), 7.46-7.48 (m, 1H), 7.54 (s, 1H), 7.61(t, J = 8.1 Hz, 1H), 7.70-7.72 (m, 1H), 7.89 (s, 1H), 8.10 (s, 1H).MS(ES⁺): m/z = 507.14 [MH⁺]. HPLC: t_(R) = 2.82 (ZQ3, Polar_5 min). 208(7R)-8-(4,4-dimethylcyclohexyl)- ¹H NMR (400 MHz, CD₃OD): δ 1.00 (d, J =5.5 2-[(7-fluoro-1H-indazol-5- Hz, 6H), 1.43-1.71 (m, 8H), 1.79 (qd, J =12.5, yl)amino]-7-methyl-5-(pyridin-3- 3.54 Hz, 1H), 1.96-2.08 (m, 2H),4.39-4.51 (m, yl)-7,8-dihydropteridin-6(5H)-one 1H), 4.55 (q, J = 6.8Hz, 1H), 7.09 (s, 1H), 7.48 (d, J = 13.1 Hz, 1H), 7.65 (dd, J = 8.2, 4.9Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.86(dt, J = 8.0, 1.7 Hz, 1H), 7.99(d, J = 2.7 Hz, 1H), 8.54 (d, J = 2.2 Hz, 1H), 8.67 (dd, J = 4.9, 1.1Hz, 1H). MS(ES⁺): m/z = 501.44[MH⁺]. HPLC: t_(R) = 0.93 min(analytical_2 min, UPLC). 209 3-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ1.01 (d, J = 5.3 dimethylcyclohexyl)-2-[(7-fluoro- Hz, 6H), 1.50-1.70(m, 7H), 1.74-1.87 (m, 1H), 1H-indazol-5-yl)amino]-7-methyl- 1.97-2.08(m, 3H), 4.41-4.50 (m, 1H), 4.54 (q, J =6-oxo-7,8-dihydropteridin-5(6H)- 6.8 Hz, 1H), 7.08 (s, 1H), 7.49 (d, J =13.3 yl]benzonitrile Hz, 1H), 7.62-7.68 (m, 1H), 7.77 (t, J = 7.9 Hz,1H), 7.80 (d, J = 1.5 Hz, 2H), 7.87-7.91 (m, 1H), 8.00 (d, J = 3.2 Hz,1H). MS(ES⁺): m/z = 525.41[MH⁺]. HPLC: t_(R) = 1.06 min (analytical_2min, UPLC). 210 (7R)-5-(3,4-dimethoxyphenyl)-8- ¹H NMR (400 MHz, CD₃OD):δ 0.94-1.07 (m, (4,4-dimethylcyclohexyl)-2-[(7- 6H), 1.42-1.52 (m, 5H),1.53-1.68 (m, 3H), fluoro-1H-indazol-5-yl)amino]-7- 1.73-1.87 (m, 1H),1.94-2.09 (m, 2H), 3.82 (s, methyl-7,8-dihydropteridin- 3H), 3.89 (s,3H), 4.27-4.45 (m, 1H), 4.50 (q, J = 6(5H)-one 6.6 Hz, 1H), 6.72-6.96(m, 2H), 7.02-7.19 (m, 2H), 7.47 (d, J = 13.1 Hz, 1H), 7.78 (d, J = 1.2Hz, 1H), 7.98 (d, J = 2.7 Hz, 1H). MS(ES⁺): m/z = 560.50[MH⁺]. HPLC:t_(R) = 1.00 min (analytical_2 min, UPLC). 211(7R)-8-(4,4-dimethylcyclohexyl)- 1H NMR (400 MHz, CD₃OD): δ 1.00 (d, J =5.31 2-[(7-fluoro-1H-indazol-5- Hz, 6H), 1.42-1.53 (m, 5H), 1.53-1.86(m, 5H), yl)amino]-5-(3-fluorophenyl)-7- 1.92-2.08 (m, 2H), 4.38-4.48(m, 1H), 4.52 (q, J = methyl-7,8-dihydropteridin- 6.7 Hz, 1H), 7.07 (s,1H), 7.11-7.19 (m, 2H), 6(5H)-one 7.28 (tdd, J = 8.5, 8.5, 2.4, 1.01 Hz,1H), 7.48 (d, J = 12.8 Hz, 1H), 7.60 (td, J = 8.2, 6.3 Hz, 1H), 7.79 (d,J = 1.5 Hz, 1H), 7.99 (d, J = 3.2 Hz, 1H). MS(ES⁺): m/z = 518.41 [MH⁺].HPLC: t_(R) = 1.06 (analytical_2 min, UPLC). 212 5-[(7R)-8-(4,4- ¹H NMR(400 MHz, DMSO-d₆) δ 0.90 (s, 3 H) dimethylcyclohexyl)-2-[(7-fluoro-0.93 (s, 3 H) 1.21-1.41 (m, 3 H) 1.44 (d, J =1H-indazol-5-yl)amino]-7-methyl- 6.8 Hz, 3 H) 1.49 (br. s., 3 H)1.67-1.81 (m, 1 6-oxo-7,8-dihydropteridin-5(6H)- H) 1.81-1.92 (m, 1 H)1.94-2.02 (m, 4 H) 3.59 yl]-2-(pyrrolidin-1-yl)benzonitrile (t, J = 6.5Hz, 4 H) 4.17-4.35 (m, 1 H) 4.47- 4.62 (m, 1 H) 6.90 (d, J = 9.3 Hz, 1H) 7.04 (s, 1 H) 7.28-7.37 (m, 1 H) 7.45-7.53 (m, 1 H) 7.55 (s, 1 H)7.81 (s, 1 H) 8.04-8.11 (m, 1 H) 9.26- 10.01 (m, 1 H) 13.15-13.83 (m, 1H). MS(ES⁺): m/z = 594.49 [MH⁺]. HPLC: t_(R) = 1.12 (UPLC, Analytical_2min). 213 (7R)-8-(4,4-dimethylcyclohexyl)- 1H NMR (400 MHz, CD₃OD) δ0.85 (s, 3 H) 2-[(7-fluoro-1H-indazol-5- 0.92 (s, 3 H) 1.14-1.25 (m, 1H) 1.28-1.50 yl)amino]-7-methyl-5-[6- (m, 2 H) 1.55 (d, J = 2.7 Hz, 1 H)1.66 (d, J = 6.8 (morpholin-4-yl)pyridin-3-yl]-7,8- Hz, 3 H) 1.68-1.75(m, 1 H) 1.90 (d, J = 2.7 Hz, dihydropteridin-6(5H)-one 2 H) 2.05-2.18(m, 1 H) 3.59-3.64 (m, 4 H) 3.77-3.85 (m, 4 H) 4.18-4.33 (m, 1 H) 4.67(d, J = 6.8 Hz, 1 H) 6.89 (s, 1 H) 7.00 (d, J = 9.0 Hz, 1 H) 7.34 (dd, J= 11.8, 1.5 Hz, 1 H) 7.53 (dd, J = 9.0, 2.5 Hz, 1 H) 7.68 (d, J = 1.7Hz, 1 H) 8.07 (d, J = 2.5 Hz, 1 H) 8.15 (d, J = 3.2 Hz, 1 H). MS(ES⁺):m/z = 586.47 [MH⁺]. HPLC: t_(R) = 0.97 (UPLC, Analytical_2 min). 214(7R)-8-(4,4-dimethylcyclohexyl)- ¹H NMR (400 MHz, CD₃OD) δ 0.83 (s, 3 H)2-[(7-fluoro-1H-indazol-5- 0.86-0.94 (m, 3 H) 1.19 (td, J = 13.0, 3.5Hz, 1 yl)amino]-7-methyl-5-[6- H) 1.26-1.47 (m, 2 H) 1.54 (dd, J = 13.3,1.7 (pyrrolidin-1-yl)pyridin-3-yl]-7,8- Hz, 1 H) 1.64 (d, J = 6.8 Hz, 3H) 1.69 (br. s., 1 dihydropteridin-6(5H)-one H) 1.74-1.86 (m, 1 H) 1.89(br. s., 1 H) 2.00- 2.10 (m, 1 H) 2.10-2.21 (m, 4 H) 3.58 (t, J = 6.3Hz, 4 H) 4.17-4.31 (m, 1 H) 4.66 (q, J = 6.6 Hz, 1 H) 6.96 (d, J = 9.3Hz, 1 H) 7.06 (s, 1 H) 7.35 (d, J = 11.8 Hz, 1 H) 7.65-7.73 (m, 2 H)8.04 (d, J = 2.0 Hz, 1 H) 8.10-8.16 (m, 1 H). MS(ES⁺): m/z = 570.42[MH⁺]. HPLC: t_(R) = 0.90 (UPLC, Analytical_2 min). 215(7R)-8-(4,4-dimethylcyclohexyl)- ¹H NMR (400 MHz, CDCl₃) δ 0.91 (s, 3 H)0.96 2-[(7-fluoro-1H-indazol-5- (s, 3 H) 1.22-1.32 (m, 1 H) 1.36-1.45(m, 1 yl)amino]-7-methyl-5-[6- H) 1.51 (dd, J = 13.3, 2.78 Hz, 1 H) 1.62(dd, (piperidin-1-yl)pyridin-3-yl]-7,8- J = 13.3, 2.7 Hz, 1 H) 1.68 (d,J = 6.8 Hz, 3 H) dihydropteridin-6(5H)-one 1.69-1.84 (m, 8 H) 1.94-2.11(m, 2 H) 3.35 (dt, J = 3.2, 1.6 Hz, 1 H) 3.61-3.70 (m, 4 H) 4.30-4.44(m, 1 H) 6.89 (d, J = 9.0 Hz, 1 H) 6.98-7.02 (m, 1 H) 7.34-7.41 (m, 2 H)7.71 (d, J = 1.5 Hz, 1 H) 7.96 (d, J = 2.7 Hz, 1 H) 8.05- 8.11 (m, 1 H).MS(ES⁺): m/z = 584.42 [MH⁺]. HPLC: t_(R) = 1.11 (UPLC, Analytical_2min).

Examples 207-215 were prepared according to procedures similar to thepreparation of Example 18, using corresponding starting materials andintermediates. For example, for the synthesis of example 209,4,4-dimethylcyclohexanone and D-alanine methyl ester hydrochloride wasused in the step a of the synthesis, (3-cyanophenyl)boronic acid wasused in the step d of the synthesis and 7-fluoro-1H-indazol-5-amine wasused in the step e of the synthesis.

Ex.# Chemical Name Analytical data 216 3-[(7R)-8-cyclopentyl-2-[(4- ¹HNMR (CDCl₃, 300 MHz) δ 1.46 (d, J = 6.9 Hz,fluoro-1H-indazol-5-yl)amino]- 3H), 1.61-1.76 (m, 6H), 1.95-2.10 (m,2H), 4.37- 7-methyl-6-oxo-7,8- 4.49 (m, 2H), 6.80 (s, 1H), 7.11 (s, 1H),7.21- dihydropteridin-5(6H)- 7.24 (m, 1H), 7.51-7.54 (m, 1H), 7.60-7.66(m, yl]benzonitrile 2H), 7.72-7.74 (m, 1H), 8.00-8.06 (m, 1H), 8.12 (brs, 1H), 10.15 (br s, 1H). MS(ES⁺): m/z = 483.14 [MH⁺]. HPLC: t_(R) =2.43 (ZQ3, Polar_5 min). 217 3-[(7R)-8-cyclopentyl-7-ethyl-2- ¹H NMR(400 MHz, CD₃OD): δ 8.08 (d, J = 1.0 [(7-fluoro-1H-indazol-5- Hz, 1H),7.93 (td, J = 1.3, 7.8 Hz, 1H), 7.80-7.84 yl)amino]-6-oxo-7,8- (m, 2H),7.76-7.80 (m, 1H), 7.66-7.72 (m, 1H), dihydropteridin-5(6H)- 7.63 (d, J= 8.8 Hz, 1H), 7.37 (dd, J = 1.8, 8.8 yl]benzonitrile Hz, 1H), 6.67 (s,1H), 4.56 (dd, J = 3.5, 6.8 Hz, 1H), 4.21 (t, J = 8.8 Hz, 1H), 1.84-2.17(m, 6H), 1.45 (br. s., 4H), 1.03 (t, J = 7.5 Hz, 3H). MS (ES⁺): m/z =497.45 [MH⁺]. UPLC: t_(R) = 0.92 min (TOF: polar_2 min). 2183-[(7R)-8-cyclopentyl-2-[(7- ¹H NMR (400 MHz, CD₃OD): δ 8.07 (d, J = 0.8fluoro-1H-indazol-5-yl)amino]- Hz, 1H), 7.93 (td, J = 1.3, 7.8 Hz, 1H),7.75-7.85 7-(hydroxymethyl)-6-oxo-7,8- (m, 3H), 7.67-7.73 (m, 1H), 7.62(d, J = 8.8 Hz, dihydropteridin-5(6H)- 1H), 7.38 (dd, J = 2.0, 8.8 Hz,1H), 4.59 (s, 1H), yl]benzonitrile 4.24 (t, J = 8.7 Hz, 1H), 3.95-4.14(m, 2H), 1.86- 2.18 (m, 4H), 1.46 (d, J = 15.2 Hz, 4H). MS (ES⁺): m/z =499.44 [MH⁺]. UPLC: t_(R) = 0.74 min (TOF: polar_2 min). 2193-[(7R)-8-cyclopentyl-2-[(7- ¹H NMR (400 MHz, CD₃OD): δ 1.48 (d, J =6.82 fluoro-1H-indazol-5-yl)amino]- Hz, 3H), 1.59-1.71 (m, 2H),1.75-1.95 (m, 4H), 7-methyl-6-oxo-7,8- 1.99-2.18 (m, 2H), 4.41-4.61 (m,2H), 7.05 (s, dihydropteridin-5(6H)- 1H), 7.45 (d, J = 13.1 Hz, 1H),7.61-7.68 (m, yl]benzonitrile 1H), 7.70-7.77 (m, 2H), 7.79 (s, 1H), 7.86(d, J = 7.8 Hz, 1H), 7.98 (d, J = 3.2 Hz, 1H). MS(ES⁺): m/z = 483.41[MH⁺]. HPLC: t_(R) = 0.88 min (analytical_2 min, UPLC). 2203-[(7R)-8-cyclopentyl-7- ¹H NMR (400 MHz, CD₃OD): δ 8.07 (d, J = 0.8(hydroxymethyl)-2-(1H-indazol- Hz, 1H), 7.93 (td, J = 1.3, 7.8 Hz, 1H),7.75-7.85 5-ylamino)-6-oxo-7,8- (m, 3H), 7.67-7.73 (m, 1H), 7.62 (d, J =8.8 Hz, dihydropteridin-5(6H)- 1H), 7.38 (dd, J = 2.0, 8.8 Hz, 1H), 6.58(s, 1H), yl]benzonitrile 4.59 (s, 1H), 4.24 (t, J = 8.7 Hz, 1H),3.95-4.14 (m, 2H), 1.86-2.18 (m, 4H), 1.46 (d, J = 15.2 Hz, 4H). MS(ES⁺): m/z = 481.40 [MH⁺]. UPLC: t_(R) = 0.66 min (TOF: polar_2 min).221 3-[(7S)-8-cyclopentyl-2-[(7- ¹H NMR (400 MHz, CD₃OD): δ 7.99 (d, J =3.0 fluoro-1H-indazol-5-yl)amino]- Hz, 1H), 7.89 (td, J = 1.3, 8.0 Hz,1H), 7.72-7.78 7-(fluoromethyl)-6-oxo-7,8- (m, 3H), 7.63-7.68 (m, 1H),7.41 (d, J = 13.6 Hz, dihydropteridin-5(6H)- 1H), 6.95 (s, 1H),4.77-4.83 (m, 1H), 4.62-4.75 yl]benzonitrile (m, 2H), 4.48 (t, J = 8.7Hz, 1H), 2.17 (dd, J = 3.4, 8.0 Hz, 1H), 2.02 (t, J = 8.2 Hz, 2H), 1.87-1.97 (m, 1H), 1.71-1.82 (m, 2H), 1.57-1.68 (m, 2H). MS (ES⁺): m/z =501.39 [MH⁺]. UPLC: t_(R) = 0.86 min (TOF: polar_2 min). 2223-[(7S)-8-cyclopentyl-7- ¹H NMR (400 MHz, CD₃OD): δ 7.96-7.99 (m,(fluoromethyl)-2-(1H-indazol-5- 1H), 7.94 (s, 1H), 7.89 (td, J = 1.3,8.0 Hz, 1H), ylamino)-6-oxo-7,8- 7.74-7.80 (m, 2H), 7.65 (ddd, J = 1.1,2.0, 8.0 dihydropteridin-5(6H)- Hz, 1H), 7.44-7.47 (m, 2H), 6.92 (s,1H), 4.62- yl]benzonitrile 4.84 (m, 2H), 4.37-4.48 (m, 1H), 1.87-2.17(m, 5H), 1.66-1.77 (m, 2H), 1.53-1.63 (m, 2H). MS (ES⁺): m/z = 483.32[MH⁺]. UPLC: t_(R) = 0.79 min (TOF: polar_2 min).

Examples 216-220 were prepared according to procedures similar to thepreparation of Example 18, using corresponding starting materials andintermediates. For example, for the synthesis of example 218, methylD-serinate and cyclopentanone were used in the step a of the synthesis,(3-cyanophenyl)boronic acid was used in the step d of the synthesis and7-fluoro-1H-indazol-5-amine was used in the step e of the synthesis.

Example 221 was prepared according to chemistry shown below:

Step f:3-[(7S)-8-cyclopentyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-(fluoromethyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile

This compound was prepared from3-[(7S)-2-chloro-8-cyclopentyl-7-(fluoromethyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrileand 7-fluoro-1H-indazol-5-amine, according to procedures similar to stepe for the preparation of Example 18.

Step e:3-[(7S)-2-chloro-8-cyclopentyl-7-(fluoromethyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile

To a stirred solution of3-[(7R)-2-chloro-8-cyclopentyl-7-(hydroxymethyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile(94 mg, 0.24 mmol) in anhydrous DCM (3 mL) was added diethylaminosulfurtrifluoride (39 μL, 0.29 mmol) at −78° C. under nitrogen. The mixturewas allowed to warm to rt and stirred for 18 h. The mixture was thencooled to 0° C. and quenched by saturated aqueous NaHCO₃ solution. Themixture was extracted with DCM (30 mL×2) and the combined organic layerswere dried over Na₂SO₄, concentrated in vacuo to give a crude residue,which was purified using a silica gel flash chromatography [eluent:0-50% EtOAc/Heptane] to afford the desired compound (24 mg, 25%). ¹H NMR(400 MHz, CD₃OD): δ 7.89-7.94 (m, 1H), 7.74-7.80 (m, 2H), 7.61-7.66 (m,1H), 7.01 (s, 1H), 4.87-5.00 (m, 1H), 4.70-4.83 (m, 1H), 4.31 (quin,J=8.4 Hz, 1H), 2.08-2.19 (m, 2H), 1.97-2.07 (m, 4H), 1.61-1.76 (m, 2H).MS (ES⁺): m/z=386.32/388.29 [MH⁺]. UPLC: t_(R)=1.33 min (TOF: polar_2min).

3-[(7R)-2-Chloro-8-cyclopentyl-7-(hydroxymethyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile:this intermediate was prepared during synthesis of example 218. Examples222 were prepared according to procedures similar to the preparation ofExample 221, using corresponding starting materials and intermediates.More specifically, 1H-indazol-5-amine was used in the step f of thesynthesis.

Examples 223 and 224 were prepared as cis/trans mixtures, according toprocedures similar to the preparation of Example 18, using correspondingstarting materials and intermediates, followed by separation bySupercritical Fluid Chromatography (SFC). More specifically,4-methoxycyclohexanone and D-Alanine methyl ester hydrochloride wereused in the step a of the synthesis, and 7-fluoro-1H-indazol-5-amine wasused in the step e of the synthesis. Examples 225-235 were preparedaccording to procedures similar to the preparation of Example 18, using4-methoxycyclohexanone, D-alanine methyl ester hydrochloride and othercorresponding starting materials and intermediates, followed bySupercritical Fluid Chromatography (SFC) to give pure isomers. Forexample, for the synthesis of example 225, (3,4-dimethoxyphenyl)boronicacid was used during the synthesis.

Ex. # Chemical Name Analytical data 223 3-[(7R)-2-[(7-fluoro-1H- ¹H NMR(400 MHz, CD₃OD): δ 1.49 (d, J = 6.8 Hz, indazol-5-yl)amino]-8-(cis-4-3H), 1.56-1.69 (m, 3H), 1.85-2.03 (m, 2H), 2.07- methoxycyclohexyl)-7-2.22 (m, 3H), 3.37 (d, J = 0.5 Hz, 3H), 3.53 (br. s., methyl-6-oxo-7,8-1H), 4.44-4.51 (m, 1H), 4.51-4.59 (m, 1H), 7.07 (s,dihydropteridin-5(6H)- 1H), 7.51 (d, J = 13.1 Hz, 1H), 7.64 (d, J = 8.0Hz, yl]benzonitrile 1H), 7.71-7.76 (m, 1H), 7.77-7.81 (m, 2H), 7.87 (d,J = 7.5 Hz, 1H), 7.99 (d, J = 3.0 Hz, 1H). MS(ES⁺): m/z = 527.34[MH⁺].HPLC: t_(R) = 0.86 min (analytical_2 min, UPLC). 2243-[(7R)-2-[(7-fluoro-1H- ¹H NMR (400 MHz, CD₃OD): δ 1.29-1.44 (m, 2H),indazol-5-yl)amino]-8-(trans- 1.48 (d, J = 6.8 Hz, 3H), 1.65-2.03 (m,3H), 2.21 (d, 4-methoxycyclohexyl)-7- J = 11.3 Hz, 3H), 3.10-3.24 (m,1H), 3.35 (s, 3H), methyl-6-oxo-7,8- 4.27-4.41 (m, 1H), 4.45 (q, J = 6.6Hz, 1H), 7.07 (s, dihydropteridin-5(6H)- 1H), 7.44 (d, J = 12.6 Hz, 1H),7.61 (d, J = 8.0 Hz, yl]benzonitrile 1H), 7.69-7.78 (m, 3H), 7.84 (d, J= 8.0 Hz, 1H), 7.99 (d, J = 3.0 Hz, 1H). MS(ES⁺): m/z = 527.30 [MH⁺].HPLC: t_(R) = 0.77 min (analytical_2 min, UPLC). 225 (7R)-5-(3,4- ¹H NMR(400 MHz, CD₃OD): δ 8.01 (d, J = 2.8 Hz, dimethoxyphenyl)-2-[(7- 1H),7.76 (d, J = 1.5 Hz, 1H), 7.43 (d, J = 12.9 Hz, fluoro-1H-indazol-5-1H), 7.11 (d, J = 8.6 Hz, 1H), 7.07 (s, 1H), 6.78- yl)amino]-8-(trans-4-6.89 (m, 2H), 4.44 (q, J = 6.8 Hz, 1H), 4.25-4.38 methoxycyclohexyl)-7-(m, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.34-3.36 (m,methyl-7,8-dihydropteridin- 3H), 3.11-3.22 (m, 1H), 2.13-2.25 (m, 3H),2.01 6(5H)-one (dd, J = 3.0, 12.6 Hz, 1H), 1.74-1.90 (m, 2H), 1.47 (d, J= 6.8 Hz, 3H), 1.27-1.43 (m, 2H). MS (ES⁺): m/z = 562.25 [MH⁺]. UPLC: tR= 0.77 min (TOF: polar_2 min). 226 (7R)-5-(3,4- ¹H NMR (400 MHz, CD₃OD):δ 1.48 (d, J = 6.57 dimethoxyphenyl)-2-[(7- Hz, 3H), 1.54-1.69 (m, 3H),1.84-2.04 (m, 2H), fluoro-1H-indazol-5- 2.08-2.22 (m, 3H), 3.35-3.40 (m,3H), 3.53 (br. s., yl)amino]-8-(cis-4- 1H), 3.83 (s, 3H), 3.90 (s, 3H),4.42-4.49 (m, 1H), methoxycyclohexyl)-7- 4.49-4.56 (m, 1H), 6.76-6.91(m, 2H), 7.03-7.16 (m, methyl-7,8-dihydropteridin- 2H), 7.50 (d, J =13.14 Hz, 1H), 7.77 (s, 1H), 7.99 6(5H)-one (d, J = 2.27 Hz, 1H).MS(ES⁺): m/z = 562.20[MH⁺]. HPLC: t_(R) = 0.82 min (analytical_2 min,UPLC). 227 (7R)-2-[(7-fluoro-1H-indazol- ¹H NMR (400 MHz, CD₃OD): δ 1.50(d, J = 6.82 5-yl)amino]-8-(cis-4- Hz, 3H), 1.56-1.70 (m, 3H), 1.84-2.04(m, 2H), methoxycyclohexyl)-7- 2.05-2.21 (m, 3H), 3.37 (s, 3H),3.36-3.39 (m, 3H), methyl-5-(pyridin-3-yl)-7,8- 3.53 (br. s., 1H),4.46-4.53 (m, 1H), 4.56 (br. s., dihydropteridin-6(5H)-one 1H), 7.10(br. s., 1H), 7.51 (d, J = 13.14 Hz, 1H), 7.65 (dd, J = 8.08, 4.80 Hz,1H), 7.78 (d, J = 1.26 Hz, 1H), 7.86 (d, J = 8.08 Hz, 1H), 7.99 (d, J =2.53 Hz, 1H), 8.54 (br. s., 1H), 8.67 (d, J = 4.04 Hz, 1H). MS(ES⁺): m/z= 503.14[MH⁺]. HPLC: t_(R) = 0.72 min (analytical_2 min, UPLC). 2283-[(7R)-8-(cis-4- ¹H NMR (400 MHz, CD₃OD): δ 1.49 (d, J = 6.82 Hz,methoxycyclohexyl)-7- 3H), 1.57-1.71 (m, 3H), 1.83-2.21 (m, 5H), 3.38(d, methyl-6-oxo-2-[(2-oxo-2,3- J = 1.01 Hz, 3H), 3.55 (br. s., 1H),4.49 (q, J = 6.57 dihydro-1,3-benzoxazol-6- Hz, 2H), 6.97 (d, J = 8.34Hz, 1H), 7.06 (s, 1H), yl)amino]-7,8- 7.14-7.20 (m, 1H), 7.64 (d, J =8.08 Hz, 1H), 7.71- dihydropteridin-5(6H)- 7.76 (m, 1H), 7.76-7.80 (m,1H), 7.84-7.91 (m, 2H). yl]benzonitrile MS(ES⁺): m/z = 526.36[MH⁺].HPLC: t_(R) = 0.80 min (analytical_2 min, UPLC). 229 3-[(7R)-8-(trans-4-¹H NMR (400 MHz, CD₃OD): δ 1.32-1.44 (m, 2H), methoxycyclohexyl)-7- 1.48(d, J = 6.8 Hz, 3H), 1.72-1.82 (m, 1H), 1.83-methyl-6-oxo-2-[(2-oxo-2,3- 1.93 (m, 1H), 1.95-2.06 (m, 1H), 2.16-2.29(m, 3H), dihydro-1,3-benzoxazol-6- 3.20-3.28 (m, 1H), 3.36-3.44 (m, 3H),4.28-4.38 (m, yl)amino]-7,8- 1H), 4.46 (q, J = 6.6 Hz, 1H), 6.98 (d, J =8.3 Hz, dihydropteridin-5(6H)- 1H), 7.06 (s, 1H), 7.23 (dd, J = 8.3, 2.0Hz, 1H), yl]benzonitrile 7.62 (d, J = 8.0 Hz, 1H), 7.69-7.78 (m, 3H),7.82- 7.89 (m, 1H). MS(ES⁺): m/z = 526.31 [MH⁺]. HPLC: t_(R) = 0.75 min(analytical_2 min, UPLC). 230 3-[(7R)-8-(trans-4- ¹H NMR (400 MHz,CD₃OD): δ 1.29-1.44 (m, 2H), methoxycyclohexyl)-7- 1.50 (d, J = 6.82 Hz,3H), 1.74-2.07 (m, 3H), 2.23- methyl-6-oxo-2-(1H- 2.33 (m, 3H),3.20-3.20 (m, 1H), 3.40 (d, J = 0.7 pyrazolo[3,4-c]pyridin-5- Hz, 3H),4.39-4.55 (m, 2H), 7.13 (s, 1H), 7.66 (d, J =ylamino)-7,8-dihydropteridin- 8.0 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H),7.80 (s, 1H), 5(6H)-yl]benzonitrile 7.88 (d, J = 7.5 Hz, 1H), 8.09 (s,1H), 8.40 (s, 1H), 8.75 (s, 1H). MS(ES⁺): m/z = 510.22 [MH⁺]. HPLC:t_(R) = 0.77 min (analytical_2 min, UPLC). 231 3-[(7R)-8-(trans-4- ¹HNMR (400 MHz, CD₃OD): δ 1.33 (d, J = 2.0 Hz, methoxycyclohexyl)-7- 2H),1.48 (d, J = 6.5 Hz, 3H), 1.72-1.88 (m, 2H), methyl-6-oxo-2-(1H-1.93-2.07 (m, 1H), 2.17 (d, J = 7.5 Hz, 3H), 3.08-pyrazolo[3,4-b]pyridin-5- 3.18 (m, 1H), 3.35 (s, 3H), 4.21-4.32 (m, 1H),4.47 ylamino)-7,8-dihydropteridin- (q, J = 6.6 Hz, 1H), 7.06 (s, 1H),7.65 (d, J = 8.0 5(6H)-yl]benzonitrile Hz, 1H), 7.75 (t, J = 7.8 Hz,1H), 7.78-7.79 (m, 1H), 7.88 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 8.51 (d,J = 2.2 Hz, 1H), 8.61 (d, J = 2.2 Hz, 1H). MS(ES⁺): m/z = 510.72[MH⁺].HPLC: t_(R) = 0.69 min (analytical_2 min, UPLC). 2323-[(7R)-2-[(3,5-difluoro-4- ¹H NMR (400 MHz, CD₃OD): δ 7.84-7.91 (m,1H), hydroxyphenyl)amino]-8- 7.72-7.82 (m, 2H), 7.64 (s, 1H), 7.25 (d, J= 10.4 (trans-4- Hz, 1H), 7.03-7.11 (m, 1H), 6.19 (s, 1H), 4.43-4.60methoxycyclohexyl)-7- (m, 1H), 4.24-4.43 (m, 1H), 3.38 (d, J = 2.8 Hz,methyl-6-oxo-7,8- 3H), 2.19-2.27 (m, 2H), 2.07-2.16 (m, 1H), 1.93-dihydropteridin-5(6H)- 2.07 (m, 1H), 1.73-1.91 (m, 2H), 1.21-1.54 (m,6H). yl]benzonitrile. MS (ES⁺): m/z = 521.62 [MH⁺]. UPLC: t_(R) = 0.87min (TOF: polar_2 min). 233 (7R)-2-[(7-fluoro-1H-indazol- MS(ES⁺): m/z =601.70[MH⁺]. HPLC: t_(R) = 0.66 min 5-yl)amino]-8-(trans-4-(analytical_2 min, UPLC). methoxycyclohexyl)-7- methyl-5-[6-(4-methylpiperazin-1-yl)pyridin- 3-yl]-7,8-dihydropteridin- 6(5H)-one 2342-methoxy-5-[(7R)-8-(trans- ¹H NMR (400 MHz, CD₃OD): δ 8.60 (d, J = 2.5Hz, 4-methoxycyclohexyl)-7- 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.03 (s, 1H),7.65 (d, methyl-6-oxo-2-(1H- J = 2.5 Hz, 1H), 7.56 (dd, J = 2.3, 8.8 Hz,1H), 7.35 pyrazolo[3,4-b]pyridin-5- (d, J = 9.1 Hz, 1H), 7.08 (s, 1H),4.45 (q, J = 6.8 ylamino)-7,8-dihydropteridin- Hz, 1H), 4.16-4.31 (m,1H), 4.03 (s, 3H), 3.32-3.36 5(6H)-yl]benzonitrile (m, 3H), 3.05-3.20(m, 1H), 2.08-2.24 (m, 3H), 1.99 (dd, J = 3.2, 12.5 Hz, 1H), 1.68-1.87(m, 2H), 1.46 (d, J = 6.8 Hz, 3H), 1.21-1.39 (m, 2H). MS (ES⁺): m/z =540.43 [MH⁺]. UPLC: t_(R)= 0.73 min (TOF: polar_2 min). 2352-methoxy-5-[(7R)-8-(trans- 1H NMR (400 MHz, CD₃OD) δ 7.71 (d, J = 1.8Hz, 4-methoxycyclohexyl)-7- 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.52-7.58 (m,1H), methyl-6-oxo-2-[(2-oxo-2,3- 7.35 (d, J = 9.1 Hz, 1H), 7.22 (dd, J =2.0, 8.3 Hz, dihydro-1,3-benzoxazol-6- 1H), 7.06 (s, 1H), 6.98 (d, J =8.6 Hz, 1H), 4.45 (q, yl)amino]-7,8- J = 6.7 Hz, 1H), 4.31 (t, J = 12.0Hz, 1H), 4.03 (s, dihydropteridin-5(6H)- 3H), 3.38 (s, 3H), 2.17-2.26(m, 3H), 2.02 (dd, J = yl]benzonitrile 2.7, 10.0 Hz, 1H), 1.79 (br. s.,2H), 1.42 (br. s., 4H), 1.32-1.41 (m, 2H). MS (ES⁺): m/z = 556.30 [M +H⁺]. UPLC: t_(R) = 0.78 min (TOF: Polar_2 min).

Examples 236-252 were prepared according to procedures similar to thepreparation of Example 18, using 4-methylcyclohexanone, D-alanine methylester hydrochloride and other corresponding starting materials andintermediates, followed by Supercritical Fluid Chromatography (SFC) togive pure isomers. For example, for the synthesis of example 238,(3,4-dimethoxyphenyl)boronic acid and 7-fluoro-1H-indazol-5-amine wereused during the synthesis.

Ex. # Chemical Name Analytical data 236 3-[(7R)-2-[(7-fluoro-1H- ¹H NMR(400 MHz, CD₃OD) δ 7.98 (d, J = 3.3 Hz, indazol-5-yl)amino]-7- 1H),7.84-7.89 (m, 1H), 7.79 (d, J = 1.3 Hz, 2H), methyl-8-(cis-4- 7.74 (t, J= 7.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), methylcyclohexyl)-6-oxo- 7.47(dd, J = 1.3, 13.1 Hz, 1H), 7.07 (s, 1H), 4.41-7,8-dihydropteridin-5(6H)- 4.56 (m, 2H), 1.94-2.11 (m, 3H), 1.65-1.89(m, 5H), yl]benzonitrile 1.59 (d, J = 12.1 Hz, 1H), 1.49 (d, J = 6.6 Hz,3H), 1.06 (d, J = 7.1 Hz, 3H). MS (ES⁺): m/z = 511.20 [M + H]⁺. UPLC:t_(R) = 0.97 min (TOF: Polar_2 min). 237 3-[(7R)-2-[(7-fluoro-1H- ¹H NMR(400 MHz, CD₃OD) δ 7.98 (d, J = 3.3 Hz, indazol-5-yl)amino]-7- 1H),7.84-7.89 (m, 1H), 7.71-7.81 (m, 3H), 7.64 (d, J = methyl-8-(trans-4-8.1 Hz, 1H), 7.47 (d, J = 13.1 Hz, 1H), 7.05 (s,methylcyclohexyl)-6-oxo- 1H), 4.37-4.52 (m, 2H), 2.16 (dd, J = 2.3, 9.3Hz, 7,8-dihydropteridin-5(6H)- 1H), 1.75-1.92 (m, 4H), 1.63-1.74 (m,1H), 1.40- yl]benzonitrile 1.50 (m, 4H), 1.13-1.24 (m, 2H), 0.96 (d, J =6.6 Hz, 3H). MS (ES⁺): m/z = 511.21 [M + H]⁺. UPLC: t_(R) = 0.96 min(TOF: polar_2 min). 238 (7R)-5-(3,4- 1H NMR (400 MHz, CD₃OD): δ 1.06 (d,J = 7.1 Hz, dimethoxyphenyl)-2-[(7- 3H), 1.51 (d, J = 6.8 Hz, 3H), 1.61(d, J = 11.3 Hz, fluoro-1H-indazol-5- 1H), 1.65-1.90 (m, 5H), 1.94-2.13(m, 3H), 3.84 (s, yl)amino]-7-methyl-8-(cis-4- 3H), 3.91 (s, 3H), 4.46(t, J = 11.6 Hz, 1H), 4.51- methylcyclohexyl)-7,8- 4.58 (m, 1H),6.77-6.92 (m, 2H), 7.08 (s, 1H), 7.11- dihydropteridin-6(5H)-one 7.12(m, 1H), 7.48 (d, J = 12.8 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 8.00 (d, J= 3.0 Hz, 1H). MS(ES⁺): m/z = 546.34 [MH⁺]. HPLC: t_(R) = 0.94(analytical_2 min, UPLC). 239 (7R)-5-(3,4- 1H NMR (400 MHz, CD₃OD): δ0.93 (d, J = 6.3 Hz, dimethoxyphenyl)-2-[(7- 3H), 1.05-1.23 (m, 2H),1.29 (br. s., 1H), 1.52 (d, J = fluoro-1H-indazol-5- 6.8 Hz, 3H),1.68-2.02 (m, 5H), 2.12 (d, J = 11.8 Hz, yl)amino]-7-methyl-8-(trans-1H), 3.83 (s, 3H), 3.90 (s, 3H), 4.33 (br. s., 1H),4-methylcyclohexyl)-7,8- 4.51 (d, J = 6.8 Hz, 1H), 6.73-6.91 (m, 2H),6.98 (s, dihydropteridin-6(5H)-one 1H), 7.12 (d, J = 8.5 Hz, 1H), 7.42(d, J = 12.8 Hz, 1H), 7.75 (d, J = 1.0 Hz, 1H), 8.03 (br. s., 1H).MS(ES⁺): m/z = 545.99 [MH⁺]. HPLC: t_(R) = 0.93 (analytical_2 min,UPLC). 240 (7R)-2-[(7-fluoro-1H- 1H NMR (400 MHz, CD₃OD): δ 1.03 (d, J =7.0 Hz, indazol-5-yl)amino]-7- 3H), 1.55 (d, J = 6.5 Hz, 3H), 1.59-2.02(m, 8H), methyl-8-(cis-4- 2.04-2.12 (m, 1H), 4.35-4.51(m, 1H), 4.58 (q,J = methylcyclohexyl)-5- 6.8 Hz, 1H), 7.05 (s, 1H), 7.45 (d, J = 12.6Hz, 1H), (pyridin-3-yl)-7,8- 7.66 (dd, J = 8.0, 4.8 Hz, 1H), 7.77 (d, J= 1.5 Hz, dihydropteridin-6(5H)-one 1H), 7.82-7.91 (m, 1H), 8.02 (br.s., 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.68 (dd, J = 4.8, 1.2 Hz, 1H).MS(ES⁺): m/z = 487.10 [MH⁺]. HPLC: t_(R) = 0.86 (analytical_2 min,UPLC). 241 (7R)-2-[(7-fluoro-1H- 1H NMR (400 MHz, CD₃OD): δ 0.83 (d, J =5.8 Hz, indazol-5-yl)amino]-7- 3H), 1.05 (d, J = 9.0 Hz, 3H), 1.63-1.73(m, 4H), methyl-8-(cis-4- 1.73-1.93 (m, 3H), 1.94-2.10 (m, 2H), 4.09 (t,J = methylcyclohexyl)-5- 11.2 Hz, 1H), 4.66 (d, J = 7.0 Hz, 1H), 6.84(s, 1H), (pyridin-3-yl)-7,8- 7.29 (dd, J = 11.3, 1.2 Hz, 1H), 7.66 (d, J= 1.0 Hz, dihydropteridin-6(5H)-one 1H), 7.72-7.86 (m, 1H), 8.00 (d, J =8.3 Hz, 1H), 8.17 (d, J = 3.0 Hz, 1H), 8.58-8.84 (m, 2H). MS(ES⁺): m/z =487.10 [MH⁺]. HPLC: t_(R) = 0.86 (analytical_2 min, UPLC). 242(7R)-2-[(7-fluoro-1H- ¹H NMR (400 MHz, CD₃OD): δ 0.96 (d, J = 3.7 Hz,indazol-5-yl)amino]-7- 3H), 1.12-1.30 (m, 2H), 1.47 (d, J = 3.5 Hz, 4H),methyl-8-(trans-4- 1.65 (d, J = 12.6 Hz, 1H), 1.76-1.96 (m, 4H), 2.19methylcyclohexyl)-5-[6-(4- (d, J = 11.6 Hz, 1H), 2.38 (d, J = 2.7 Hz,3H), 2.60 methylpiperazin-1- (br. s., 4H), 3.66 (br. s., 4H), 4.34-4.51(m, 2H), 6.93 yl)pyridin-3-yl]-7,8- (d, J = 8.8 Hz, 1H), 7.16 (d, J =3.2 Hz, 1H), 7.33- dihydropteridin-6(5H)-one 7.51 (m, 2H), 7.68-7.82 (m,1H), 7.97 (d, J = 11.1 Hz, 2H). MS(ES⁺): m/z = 585.73[MH⁺]. HPLC: t_(R)= 0.69 min (analytical_2 min, UPLC). 243 3-[(7R)-2-[(3,5-difluoro-4- ¹HNMR (400 MHz, CD₃OD): δ 7.86 (d, J = 7.6 Hz, hydroxyphenyl)amino]-7-1H), 7.71-7.79 (m, 2H), 7.63 (d, J = 8.1 Hz, 1H), methyl-8-(trans-4-7.22-7.32 (m, 2H), 7.05 (s, 1H), 4.39-4.53 (m, 2H),methylcyclohexyl)-6-oxo- 2.12-2.22 (m, 1H), 1.77-1.95 (m, 4H), 1.62-1.74(m, 7,8-dihydropteridin-5(6H)- 1H), 1.43-1.53 (m, 4H), 1.17-1.32 (m,2H), 0.97 (d, J = yl]benzonitrile. 6.3 Hz, 3H). MS (ES⁺): m/z = 505.63[MH⁺]. UPLC: t_(R) = 1.09 min (TOF: polar_2 min). 2442-methoxy-5-[(7R)-7- ¹H NMR (400 MHz, CD₃OD): δ 7.82 (s, 1H), 7.64methyl-8-(trans-4- (br. s., 1H), 7.55 (d, J = 9.1 Hz, 1H), 7.35 (d, J =8.6 methylcyclohexyl)-6-oxo-2- Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.06(s, 1H), 6.97 [(2-oxo-2,3-dihydro-1,3- (d, J = 8.6 Hz, 1H), 4.47 (q, J =6.2 Hz, 1H), 4.39 (t, benzoxazol-6-yl)amino]-7,8- J = 12.3 Hz, 1H), 4.03(s, 3H), 2.15 (s, 2H), 1.84- dihydropteridin-5(6H)- 1.94 (m, 3H),1.62-1.83 (m, 2H), 1.47 (d, J = 6.8 Hz, yl]benzonitrile 4H), 1.14-1.37(m, 3H), 0.98 (d, J = 6.3 Hz, 3H). MS (ES⁺): m/z = 540.62 [MH⁺]. UPLC:t_(R) = 0.94 min (TOF: polar_2 min). 245 2-Methoxy-5-[(7R)-7- ¹H NMR(400 MHz, CD₃OD): δ 8.60 (s, 1H), 8.53 (d, methyl-8-(trans-4- J = 2.5Hz, 1H), 8.01 (s, 1H), 7.65 (br. s., 1H), 7.55methylcyclohexyl)-6-oxo-2- (s, 1H), 7.36 (d, J = 9.1 Hz, 1H), 7.08 (s,1H), 4.47 (1H-pyrazolo[3,4-b]pyridin- (d, J = 6.8 Hz, 1H), 4.25-4.38 (m,1H), 4.03 (s, 3H), 5-ylamino)-7,8- 2.07-2.15 (m, 1H), 1.76-1.93 (m, 4H),1.47 (d, J = dihydropteridin-5(6H)- 6.6 Hz, 3H), 1.29 (br. s., 2H), 1.15(br. s., 2H), 0.94 yl]benzonitrile (d, J = 6.6 Hz, 3H). MS (ES⁺): m/z =524.71 [MH⁺]. UPLC: t_(R) = 0.91 min (TOF: polar_2 min). 2462-Ethoxy-5-[(7R)-7-methyl- ¹H NMR (400 MHz, CD₃OD): δ 8.60 (d, J = 2.3Hz, 8-(trans-4- 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.01 (s, 1H), 7.64 (s,methylcyclohexyl)-6-oxo-2- 1H), 7.53 (d, J = 7.1 Hz, 1H), 7.33 (d, J =8.8 Hz, (1H-pyrazolo[3,4-b]pyridin- 1H), 7.08 (s, 1H), 4.47 (d, J = 6.8Hz, 1H), 4.30-4.38 5-ylamino)-7,8- (m, 1H), 2.11 (d, J = 12.6 Hz, 1H),1.74-1.92 (m, dihydropteridin-5(6H)- 4H), 1.64-1.73 (m, 1H), 1.50 (s,7H), 1.33-1.42 (m, yl]benzonitrile 1H), 1.26-1.32 (m, 1H), 1.06-1.20 (m,2H), 0.94 (d, J = 6.3 Hz, 3H). MS (ES⁺): m/z = 538.69 [MH⁺]. UPLC: t_(R)= 0.96 min (TOF: polar_2 min). 247 2-Ethoxy-5-[(7R)-7-methyl- ¹H NMR(400 MHz, CD₃OD): δ 7.82 (d, J = 2.0 Hz, 8-(trans-4- 1H), 7.63 (s, 1H),7.49-7.56 (m, 1H), 7.33 (d, J = 9.1 methylcyclohexyl)-6-oxo-2- Hz, 1H),7.18 (dd, J = 2.0, 8.6 Hz, 1H), 7.06 (s, 1H), [(2-oxo-2,3-dihydro-1,3-6.97 (d, J = 8.6 Hz, 1H), 4.47 (d, J = 6.8 Hz, 1H),benzoxazol-6-yl)amino]-7,8- 4.34-4.43 (m, 1H), 2.10-2.21 (m, 1H), 1.89(br. s., dihydropteridin-5(6H)- 3H), 1.74-1.84 (m, 1H), 1.66-1.74 (m,1H), 1.45- yl]benzonitrile 1.53 (m, 7H), 1.27-1.35 (m, 3H), 0.98 (d, J =6.6 Hz, 3H). MS (ES⁺): m/z = 554.67 [MH⁺]. UPLC: t_(R) = 1.00 min (TOF:polar_2 min). 248 5-[(7R)-7-methyl-8-(trans-4- ¹H NMR (400 MHz, CD₃OD):δ 8.60 (d, J = 2.3 Hz, methylcyclohexyl)-6-oxo-2- 1H), 8.54 (d, J = 2.5Hz, 1H), 8.01 (s, 1H), 7.63 (s, (1H-pyrazolo[3,4-b]pyridin- 1H), 7.51(d, J = 7.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 5-ylamino)-7,8- 1H), 7.09 (s,1H), 4.47 (q, J = 7.0 Hz, 1H), 4.32 (t, J = dihydropteridin-5(6H)-yl]-2-12.0 Hz, 1H), 2.11 (d, J = 12.4 Hz, 1H), 1.75-1.97 (propan-2- (m, 4H),1.60-1.74 (m, 1H), 1.35-1.52 (m, 11H), yloxy)benzonitrile. 1.02-1.22 (m,2H), 0.94 (d, J = 6.6 Hz, 3H). MS (ES⁺): m/z = 552.27 [MH⁺]. UPLC: t_(R)= 0.86 min (TOF: polar_2 min). 249 5-[(7R)-7-methyl-8-(trans-4- ¹H NMR(400 MHz, CD₃OD): δ 7.82 (d, J = 2.0 Hz, methylcyclohexyl)-6-oxo-2- 1H),7.62 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.35 (d, J =[(2-oxo-2,3-dihydro-1,3- 9.1 Hz, 1H), 7.18 (dd, J = 2.0, 8.6 Hz, 1H),7.07 benzoxazol-6-yl)amino]-7,8- (s, 1H), 6.97 (d, J = 8.3 Hz, 1H),4.33-4.51 (m, 2H), dihydropteridin-5(6H)-yl]-2- 2.10-2.19 (m, 1H),1.84-1.93 (m, 3H), 1.64-1.83 (m, (propan-2-yloxy)benzonitrile 2H),1.40-1.51 (m, 10H), 1.29 (s, 3H), 0.98 (d, J = 6.6 Hz, 3H). MS (ES⁺):m/z = 568.26 [MH⁺]. UPLC: t_(R) = 0.88 min (TOF: polar_2 min). 2503-[(7R)-2-[(2,2-dioxido-1,3- ¹H NMR (400 MHz, CD₃OD): δ 7.86 (d, J = 7.8Hz, dihydro-2,1-benzothiazol-5- 1H), 7.70-7.78 (m, 2H), 7.59-7.65 (m,1H), 7.54- yl)amino]-7-methyl-8- 7.57 (m, 1H), 7.44 (dd, J = 1.9, 8.5Hz, 1H), 7.01 (s, (trans-4-methylcyclohexyl)- 1H), 6.79 (d, J = 8.6 Hz,1H), 4.47 (d, J = 6.8 Hz, 6-oxo-7,8-dihydropteridin- 1H), 4.34-4.38 (m,2H), 2.09-2.17 (m, 1H), 1.89 (d, J = 5(6H)-yl]benzonitrile. 10.9 Hz,3H), 1.63-1.82 (m, 2H), 1.47 (d, J = 6.6 Hz, 4H), 1.28 (s, 1H), 1.15 (t,J = 11.7 Hz, 2H), 0.97 (d, J = 6.6 Hz, 3H). MS (ES⁺): m/z = 544.40[MH⁺]. UPLC: t_(R) = 0.95 min (TOF: polar_2 min). 2515-[(7R)-2-[(7-fluoro-1H- ¹H NMR (CDCl₃, 400 MHz): δ 0.98 (d, J = 6.0 Hz,3 indazol-5-yl)amino]-7- H), 1.19-1.26 (m, 2 H), 1.47 (d, J = 6.4 Hz, 3H), methyl-8-(trans-4- 1.54-1.64 (m, 2 H), 1.76-1.92 (m, 4 H), 2.21 (m,1 methylcyclohexyl)-6-oxo- H), 2.39 (s, 3 H), 2.66 (t, J = 4.8 Hz, 4 H),3.35 (t, J = 7,8-dihydropteridin-5(6H)- 4.8 Hz, 4 H), 4.41 (m, 1 H),4.43 (q, J = 6.4 Hz, 1 yl]-2-(4-methylpiperazin-1- H), 7.01 (s, 1 H),7.09 (d, J = 8.8 Hz, 1 H), 7.21 (s, 1 yl)benzonitrile H), 7.32 (dd, J =2.4, 8.8 Hz, 1 H), 7.43 (d, J = 2.8 Hz, 1 H), 7.45 (dd, J = 1.6, 11.6Hz, 1 H), 7.71 (d, J = 1.6 Hz, 1 H), 8.00 (d, J = 3.6 Hz, 1 H). MS(ES⁺): m/z = 609.51 [MH⁺]. HPLC: t_(R) = 0.76 min (TOF, polar_2 min).252 5-[(7R)-7-methyl-8-(trans-4- ¹H NMR (CDCl₃, 400 MHz): δ 0.99 (d, J =6.4 Hz, 3 methylcyclohexyl)-6-oxo-2- H), 1.16-1.28 (m, 2 H), 1.40-1.65(m, 2 H), 1.50 (d, J = (1H-pyrazolo[3,4-b]pyridin- 6.4 Hz, 3 H),1.77-1.97 (m, 4 H), 2.39 (m, 1 H), 5-ylamino)-7,8- 2.41 (s, 3 H), 2.69(t, J = 4.8 Hz, 4 H), 3.40 (t, J = dihydropteridin-5(6H)-yl]-2- 4.8 Hz,4 H), 4.48 (m, 1 H), 4.50 (q, J = 6.4 Hz, 1 (4-methylpiperazin-1- H),7.14 (d, J = 8.8 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 yl)benzonitrile H),7.41 (s, 1 H), 7.47 (s, 1 H), 8.02 (s, 1 H), 8.79 (d, J = 2.0 Hz, 1 H),8.99 (d, J = 2.0 Hz, 1 H), 9.52 (s, 1 H). MS (ES⁺): m/z = 592.47 [MH⁺].HPLC: t_(R) = 0.69 min (TOF, polar_2 min).

Examples 253-259 were prepared according to procedures similar to thepreparation of Example 18, using 4-(trifluoromethyl)cyclohexanone,D-alanine methyl ester hydrochloride and other corresponding startingmaterials and intermediates, followed by Supercritical FluidChromatography (SFC) to give pure isomers. For example, for thesynthesis of example 257, (3,4-dimethoxyphenyl)boronic acid and7-fluoro-1H-indazol-5-amine were used during the synthesis.

Ex. # Chemical Structure and Name Analytical data 2533-[(7R)-2-(1H-indazol-5- ¹H NMR (400 MHz, CDCl₃) δ 1.49 (d, J = 6.5 Hz,3 H) ylamino)-7-methyl-6-oxo-8- 1.57-1.68 (m, 4 H) 1.82 (dd, J = 12.6,3.2 Hz, 1 H) [trans-4- 2.00 (d, J = 12.1 Hz, 1 H) 2.12-2.24 (m, 2H)(trifluoromethyl)cyclohexyl]-7,8- 2.33 (br. s., 1 H) 4.42 (q, J = 6.6Hz, 2 H) 7.00 dihydropteridin-5(6H)- (s, 1 H) 7.19 (s, 1 H) 7.43-7.56(m, 2 H) 7.59 (s, 1 H) yl]benzonitrile 7.62-7.69 (m, 2 H) 7.75 (dt, J =7.7, 1.2 Hz, 1 H) 8.02 (d, J = 3.5 Hz, 1 H) 10.01-10.61 (m, 1 H).MS(ES⁺): m/z = 565.8 [MH⁺]. SFC: t_(R) = 22.55 min 2543-[(7R)-2-(1H-indazol-5- ¹H NMR (400 MHz, CDCl₃) δ 1.48 (d, J = 6.82 Hz,3 H) ylamino)-7-methyl-6-oxo-8-[cis- 1.57 (br. s., 3 H) 1.84 (br. s., 3H) 2.11 (br. s., 2 H) 4-(trifluoromethyl)cyclohexyl]- 2.22 (br. s., 2 H)2.34-2.49 (m, 1 H) 4.45 (d, 7,8-dihydropteridin-5(6H)- J = 6.57 Hz, 2 H)6.92 (s, 1 H) 7.18 (s, 1 H) 7.48-7.55 yl]benzonitrile (m, 2H) 7.56-7.70(m, 3 H) 7.71-7.79 (m, 1 H) 8.01 (d, J = 3.54 Hz, 1 H) 9.77-10.84 (m, 1H). MS(ES⁺): m/z = 565.8 [MH⁺]. SFC: t_(R) = 17.88 min 255(7R)-2-[(7-fluoro-1H-indazol-5- ¹H NMR (400 MHz, Pyridine-d₅) δ 10.50(s, 1H), yl)amino]-7-methyl-5-(pyridin-3- 8.97 (d, J = 2.5 Hz, 1H), 8.81(dd, J = 1.5, 4.8 Hz, yl)-8-[cis-4- 1H), 8.42-8.52 (m, 2H), 8.14 (dd, J= 1.4, 13.5 Hz, (trifluoromethyl)cyclohexyl]-7,8- 1H), 7.86-7.94 (m,1H), 7.48 (dd, J = 4.8, 8.1 Hz, dihydropteridin-6(5H)-one 1H), 5.00 (s,1H), 4.66 (q, J = 6.7 Hz, 1H), 4.44- 4.56 (m, 1H), 2.34 (d, J = 3.3 Hz,1H), 1.91-2.18 (m, 4H), 1.59-1.83 (m, 3H), 1.42-1.56 (m, 4H), 1.27-1.36(m, 1H). MS (ES⁺): m/z = 541.23 [M + H]⁺. UPLC: t_(R) = 0.87 min (TOF:polar_2 min). 256 (7R)-2-[(7-fluoro-1H-indazol-5- ¹H NMR (400 MHz,Pyridine-d₅) δ 15.18 (br. s., yl)amino]-7-methyl-5-(pyridin-3- 1H),10.56 (s, 1H), 8.98 (s, 1H), 8.82 (d, J = 4.5 yl)-8-[trans-4- Hz, 1H),8.46 (br. s., 2H), 8.14 (d, J = 13.4 Hz, 1H),(trifluoromethyl)cyclohexyl]-7,8- 7.92 (d, J = 7.8 Hz, 1H), 7.49 (dd, J= 4.8, 7.8 Hz, dihydropteridin-6(5H)-one 1H), 5.01 (br. s., 1H), 4.64(q, J = 6.6 Hz, 1H), 4.25-4.39 (m, 1H), 2.20 (d, J = 10.4 Hz, 1H), 1.91-2.12 (m, 3H), 1.68-1.86 (m, 2H), 1.29-1.65 (m, 6H). MS (ES⁺): m/z =540.86 [M + H]⁺. UPLC: t_(R) = 0.87 min (TOF: polar_2 min). 257(7R)-5-(3,4-dimethoxyphenyl)-2- ¹H NMR (400 MHz, Pyridine-d₅) δ 10.38(br. s., [(7-fluoro-1H-indazol-5- 1H), 8.39-8.53 (m, 2H), 8.16 (d, J =13.6 Hz, 1H), yl)amino]-7-methyl-8-[cis-4- 7.67 (s, 1H), 7.18-7.30 (m,2H), 4.67 (q, J = 6.6 Hz, (trifluoromethyl)cyclohexyl]-7,8- 1H),4.46-4.58 (m, 1H), 3.82 (s, 3H), 3.72 (s, 3H), dihydropteridin-6(5H)-one3.58-3.65 (m, 1H), 2.34 (br. s., 1H), 1.91-2.21 (m, 4H), 1.61-1.84 (m,3H), 1.44-1.58 (m, 4H), 1.23- 1.35 (m, 1H). MS (ES⁺): m/z = 599.98 [M +H]⁺. UPLC: t_(R) = 0.91 min (TOF: polar_2 min). 258(7R)-5-(3,4-dimethoxyphenyl)-2- ¹H NMR (400 MHz, Pyridine-d₅) δ 10.45(br. s., [(7-fluoro-1H-indazol-5- 1H), 8.40-8.51 (m, 2H), 8.16 (dd, J =1.3, 13.4 Hz, yl)amino]-7-methyl-8-[trans-4- 1H), 7.66 (s, 1H), 7.22 (s,2H), 4.65 (q, J = 6.7 Hz, (trifluoromethyl)cyclohexyl]-7,8- 1H),4.27-4.41 (m, 1H), 3.78-3.86 (m, 3H), 3.73 (s, dihydropteridin-6(5H)-one3H), 3.62 (s, 1H), 2.23 (d, J = 11.6 Hz, 1H), 1.93- 2.15 (m, 3H),1.72-1.90 (m, 2H), 1.37-1.67 (m, 6H), 1.19-1.34 (m, 1H). MS (ES⁺): m/z =599.98 [M + H]⁺. UPLC: t_(R) = 0.91 min (TOF: polar_2 min). 2593-[(7R)-2-[(3,5-difluoro-4- ¹H NMR (400 MHz, CD₃OD): δ 7.84-7.90 (m,1H), hydroxyphenyl)amino]-7-methyl- 7.71-7.80 (m, 2H), 7.63 (d, J = 8.3Hz, 1H), 7.20- 6-oxo-8-[trans-4- 7.33 (m, J = 10.6 Hz, 2H), 7.07 (s,1H), 4.50 (q, J = (trifluoromethyl)cyclohexyl]-7,8- 6.7 Hz, 1H), 4.41(tt, J = 3.6, 11.9 Hz, 1H), 2.22- dihydropteridin-5(6H)- 2.33 (m, 2H),2.08-2.18 (m, 2H), 1.91-2.08 (m, 2H), yl]benzonitrile 1.82 (dq, J = 3.2,12.4 Hz, 1H), 1.52-1.69 (m, 2H), 1.49 (d, J = 6.8 Hz, 3H). MS (ES⁺): m/z= 559.31 [MH⁺]. UPLC: t_(R) = 1.09 min (TOF: polar_2 min).

Example 260 was prepared by following procedure:

Step a: Synthesis of methyl N-1,4-dioxaspiro[4.5]dec-8-yl-D-alaninate

To a stirred mixture of D-alanine methyl ester hydrochloride (1, 12 g,85.9 mmol) in anhydrous dichloromethane (120 mL) was added potassiumacetate (8.5 g, 85.9 mmol) and the resulting reaction mixture wasstirred at rt for ten minutes. The reaction was then cooled to 10° C.and treated with 1,4-dioxaspiro[4.5]decan-8-one (2, 13.4 g, 85.9 mmol),followed by the addition of sodium triacetoxyborohydride (22.6 g, 106.6mmol) in portions over a period of ten minutes. The resulting reactionmixture was stirred at rt for 16 h. Saturated aqueous sodium bicarbonatesolution was then added to the reaction and the mixture was stirred foranother 30 minutes. Dichloromethane layer was separated and the aqueouslayer was extracted with dichloromethane (100 mL×3). Organic layers werecombined, washed with brine, dried over sodium sulfate, and evaporatedto give the crude product as colorless oil (14 g), which was used fornext step without any further purifications. ¹HNMR (300 MHz, CDCl₃): δ1.22 (d, 3H), 1.40-1.61 (m, 4H), 1.65-1.90 (m, 4H), 2.42-2.55 (m, 1H),3.42 (q, 1H), 3.72 (s, 3H), 3.98 (s, 4H).

Step b: Synthesis of methylN-(2-chloro-5-nitropyrimidin-4-yl)-N-1,4-dioxaspiro[4.5]dec-8-yl-D-alaninate

To a stirred mixture of 2,4-dichloro-5-nitropyrimidine (4, 12 g, 62.1mmol), potassium carbonate (11.7 g, 84.78 mmol) in acetone (100 mL) wasadded methyl N-1,4-dioxaspiro[4.5]dec-8-yl-D-alaninate (13.8 g, 62.1mmol) at rt. The reaction mixture was stirred for 16 h at rt. The bulkof solvent was removed under reduced pressure to give a residue, whichwas diluted with ethyl acetate (100 mL), washed with water, dried oversodium sulfate. The solvent was evaporated to give a crude material,which was then purified by silica gel flash chromatography (eluent:ethyl acetate-hexane mixture (v:v=5:95)) to afforded the desired product(10.1 g). ¹HNMR (300 MHz, CDCl₃): δ 1.55-1.64 (m, 3H), 1.70-1.99 (m,6H), 2.05-2.20 (m, 3H), 3.06-3.15 (m, 1H), 3.75 (s, 3H), 3.99 (t, 4H),8.61 (s, 1H).

Step c: Synthesis of methylN-(2-chloro-5-nitropyrimidin-4-yl)-N-(4-oxocyclohexyl)-D-alaninate

A stirred solution of methylN-(2-chloro-5-nitropyrimidin-4-yl)-N-1,4-dioxaspiro[4.5]dec-8-yl-D-alaninate(17 g, 42.5 mmol) in dioxane (450 mL, contains 1M HCl) was heated toreflux for 16 h. The bulk of solvent was then removed under reducedpressure, the crude material was neutralized with aq. NaHCO₃, andextracted with ethyl acetate (300 mL×3). Organic layers were combined,dried over sodium sulfate, and evaporated to give the crude material,which was then purified by silica gel column chromatography to give thedesired product (10 g). ¹HNMR (300 MHz, CDCl₃): δ 1.66 (d, J=6.9 Hz,3H), 1.99-2.18 (m, 2H), 2.34-2.57 (m, 6H), 3.56-3.59 (m, 1H), 3.76 (s,3H), 4.04 (q, J=6.9, 13.8 Hz, 1H), 8.70 (s, 1H).

Step d: Synthesis of methylN-(2-chloro-5-nitropyrimidin-4-yl)-N-(4,4-difluorocyclohexyl)-D-alaninate

To a stirred solution of triethylamine trihydrofluoride (2.72 mL, 16.7mmol) and triethylamine (1.17 mL, 8.41 mmol) in dichloromethane (30 mL)was added Xtalfluor-E (2.9 g, 12.6 mmol) at 0° C. To the solution wasthen added methylN-(2-chloro-5-nitropyrimidin-4-yl)-N-(4-oxocyclohexyl)-D-alaninate (3 g,8.37 mmol) slowly. An additional amount of Xtalfluor-E (2.9 g, 12.6mmol) was added after 3 h, and resulting mixture was stirred at rt for 9h. The reaction mixture was quenched with a 5% aqueous NaHCO₃ solution.The resulting mixture was extracted with dichloromethane (40 mL×3). Theorganic phases were combined, dried over Na₂SO₄, evaporated to give thecrude material, which was then purified by silica gel columnchromatography to give the desired product (2.2 g). ¹HNMR (300 MHz,CDCl₃): δ 1.60-1.99 (m, 6H), 2.19-2.24 (m, 3H), 3.16-3.25 (m, 3H), 3.75(s, 3H), 4.06 (q, J=6.9 Hz, 1H), 8.65 (s, 1H).

Step e: Synthesis of(7R)-2-chloro-8-(4,4-difluorocyclohexyl)-7-methyl-7,8-dihydropteridin-6(5H)-one

To a stirred solution of methylN-(2-chloro-5-nitropyrimidin-4-yl)-N-(4,4-difluorocyclohexyl)-D-alaninate(3.9 g, 9.24 mmol) in ethanol (120 mL) was added iron powder (5.12 g,91.0 mmol).

The resulting mixture was then heated to reflux. 1N aqueous hydrochloricacid (8 ml) was then added to the mixture in small portions. Thereaction mixture was refluxed for 8 h. After cooling to rt, theinsoluble material was removed by filtration, the bulk of ethanol wasevaporated to give a crude material, which was then purified by silicagel column chromatography (eluent: 5% methanol in dichloromethane) togive the desired product (2.3 g). ¹HNMR (300 MHz, CDCl₃): δ 1.43 (d,J=6.9 Hz, 3H), 1.81-2.24 (m, 8H), 4.28 (q, J=6.6 Hz, 1H), 4.43-4.51 (m,1H), 7.76 (s, 1H), 9.46 (s, 1H).

Step f: Synthesis of3-[(7R)-2-chloro-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile

To a stirred solution of(7R)-2-chloro-8-(4,4-difluorocyclohexyl)-7-methyl-7,8-dihydropteridin-6(5H)-one(1.80 g, 5.7 mmol) in dichloromethane (75 mL) was added triethylamine(8.07 ml, 57.8 mmol), cupric acetate (2.09 g, 11.56 mmol) and(3-cyanophenyl)boronic acid (1.69 g, 11.56 mmol) followed by 4 Åmolecular sieves (2 g). The reaction mixture was stirred for 48 h at rtwith an air balloon on the top. The reaction mixture was then filteredover celite to give a clear solution. The solution was washed withaqueous saturated sodium bicarbonate (50 mL×2), dried over anhydroussodium sulfate and evaporated to give a crude material, which was thenpurified by silica gel column chromatography (eluent: 2% methanol indichloromethane) to give the desired product (51%). ¹HNMR (300 MHz,CDCl₃): δ 1.50 (d, J=6.9 Hz, 3H), 1.80-2.24 (m, 8H), 4.40-4.61 (m, 2H),7.20-7.26 (m, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.55 (s, 1H), 7.69 (t, J=7.8Hz, 1H), 7.80 (d, J=8.1 Hz, 1H).

Step g: Synthesis of3-[(7R)-8-(4,4-difluorocyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile

To a solution of3-[(7R)-2-chloro-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile(208 mg, 0.5 mmol), 7-fluoro-1H-indazol-5-amine (113 mg, 0.75 mmol) intrifluoroethanol (2 mL) in a microwave reaction vial was addedtrifluoroacetic acid (171 mg). The vial was then sealed and heated in amicrowave reactor at 125° C. for 30 minutes. The reaction mixture wasthen diluted with ethyl acetate (25 mL) and washed with aqueoussaturated aq. sodium bicarbonate. The organic layer was dried (Na₂SO₄)and evaporated to give a crude material, which was then purified bysilica gel column chromatography (eluent: 2% methanol indichloromethane) to give the desired product (40%).

Examples 261-286 were prepared according to procedures similar to thepreparation of Example 260, using corresponding starting materials andintermediates. For example, for the synthesis of example 262,(3,4-dimethoxyphenyl)boronic acid was used in the step f of thesynthesis.

Ex. # Chemical Name Analytical data 260 3-[(7R)-8-(4,4- ¹H NMR (400 MHz,CD₃OD): δ 7.93-8.03 (m, difluorocyclohexyl)-2-[(7- 1H), 7.85-7.90 (m,1H), 7.71-7.81 (m, 3H), 7.65 fluoro-1H-indazol-5-yl)amino]- (d, J = 8.1Hz, 1H), 7.50 (d, J = 12.9 Hz, 1H), 7-methyl-6-oxo-7,8- 7.06-7.13 (m,1H), 4.43-4.60 (m, 2H), 1.85-2.31 dihydropteridin-5(6H)- (m, 7H),1.45-1.54 (m, 3H), 1.32 (br. s., 1H). MS yl]benzonitrile (ES⁺): m/z =533.41 [MH⁺]. UPLC: t_(R) = 0.90 min (TOF: polar_2 min). 2613-[(7R)-8-(4,4- ¹H NMR (400 MHz, CDCl₃) δ 1.26 (s, 2 H) 1.49difluorocyclohexyl)-2-(1H- (d, J = 6.8 Hz, 3 H) 1.88 (d, J = 8.5 Hz, 2H) indazol-5-ylamino)-7-methyl-6- 1.95-2.05 (m, 1 H) 2.05-2.19 (m, 1 H)2.28 (d, oxo-7,8-dihydropteridin-5(6H)- J = 7.5 Hz, 2 H) 4.42 (d, J =6.8 Hz, 2 H) 6.91 (s, yl]benzonitrile 1H) 7.20 (s, 1 H) 7.40-7.47 (m, 2H) 7.52 (d, J = 8.0 Hz, 1 H) 7.59 (s, 1 H) 7.65 (t, J = 7.9 Hz, 1 H)7.75 (dt, J = 7.8, 1.26 Hz, 1 H) 8.00 (s, 1 H) 8.03 (s, 1 H) 9.87-10.27(m, 1 H). MS(ES⁺): m/z = 515.6 [MH⁺]. 262 (7R)-8-(4,4- MS(ES⁺): m/z =568.82 (60) [MH⁺]. HPLC: t_(R) = difluorocyclohexyl)-5-(3,4- 2.46 (ZQ3,Polar_5 min). dimethoxyphenyl)-2-[(7-fluoro- 1H-indazol-5-yl)amino]-7-methyl-7,8-dihydropteridin- 6(5H)-one 263 (7R)-8-(4,4- MS(ES⁺): m/z =526.93 (80) [MH⁺]. HPLC: t_(R) = difluorocyclohexyl)-2-[(7- 2.71 (ZQ3,Polar_5 min). fluoro-1H-indazol-5-yl)amino]-5-(3-fluorophenyl)-7-methyl- 7,8-dihydropteridin-6(5H)-one 264(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ 8.67 (dd, J = 1.4,difluorocyclohexyl)-2-[(7- 4.9 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 7.99(d, J = fluoro-1H-indazol-5-yl)amino]- 2.8 Hz, 1H), 7.82-7.90 (m, 1H),7.72 (d, J = 7-methyl-5-(pyridin-3-yl)-7,8- 1.8 Hz, 1H), 7.65 (dd, J =4.8, 8.1 Hz, 1H), 7.50 dihydropteridin-6(5H)-one (d, J = 12.9 Hz, 1H),7.11 (s, 1H), 4.43-4.61 (m, 2H), 1.83-2.32 (m, 8H), 1.49 (d, J = 6.8 Hz,3H). MS (ES⁺): m/z = 509.18 [MH⁺]. UPLC: t_(R) = 0.76 min (TOF: polar_2min). 265 3-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ 7.86 (td, J = 1.3,difluorocyclohexyl)-7-methyl-6- 7.8 Hz, 1H), 7.71-7.79 (m, 2H),7.59-7.66 (m, oxo-2-[(2-oxo-2,3-dihydro-1H- 1H), 7.29 (d, J = 1.8 Hz,1H), 7.16 (dd, J = 2.0, benzimidazol-5-yl)amino]-7,8- 8.6 Hz, 1H), 7.03(s, 1H), 6.95 (d, J = 8.6 Hz, dihydropteridin-5(6H)- 1H), 4.46 (q, J =6.7 Hz, 2H), 1.78-2.28 (m, 9H), yl]benzonitrile 1.47 (d, J = 6.8 Hz,3H). MS (ES⁺): m/z = 531.34 [MH⁺]. UPLC: t_(R) = 0.75 min (TOF: polar_2min). 266 3-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ 7.86 (td, J = 1.4,difluorocyclohexyl)-7-methyl-6- 7.8 Hz, 1H), 7.71-7.80 (m, 3H),7.60-7.67 (m, oxo-2-[(2-oxo-2,3-dihydro-1,3- 1H), 7.19 (dd, J = 2.0, 8.6Hz, 1H), 7.08 (s, 1H), benzoxazol-6-yl)amino]-7,8- 6.97 (d, J = 8.3 Hz,1H), 4.41-4.56 (m, 2H), dihydropteridin-5(6H)- 1.85-2.30 (m, 8H), 1.48(d, J = 6.8 Hz, 3H). MS yl]benzonitrile (ES⁺): m/z = 533.32 [MH⁺]. UPLC:t_(R) = 0.86 min (TOF: polar_2 min). 267 3-[(7R)-8-(4,4- ¹H NMR (400MHz, CD₃OD): δ 7.84-7.89 (m, difluorocyclohexyl)-7-methyl-6- 2H),7.71-7.79 (m, 2H), 7.63 (d, J = 8.6 Hz, 1H),oxo-2-[(2-oxo-2,3-dihydro-1,3- 7.35 (dd, J = 2.3, 8.6 Hz, 1H), 7.02-7.09(m, benzothiazol-6-yl)amino]-7,8- 2H), 4.40-4.56 (m, 2H), 2.02-2.30 (m,5H), 1.86- dihydropteridin-5(6H)- 1.99 (m, 3H), 1.47 (d, J = 6.8 Hz,3H). MS (ES⁺): yl]benzonitrile m/z = 548.11 [MH⁺]. UPLC: t_(R) = 0.90min (TOF: polar_2 min). 268 3-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ8.74 (s, 1H), difluorocyclohexyl)-7-methyl-6- 8.35 (s, 1H), 8.04 (s,1H), 7.88 (d, J = 7.8 Hz, oxo-2-(1H-pyrazolo[3,4- 1H), 7.71-7.82 (m,2H), 7.66 (d, J = 8.1 Hz, 1H), c]pyridin-5-ylamino)-7,8- 7.16 (s, 1H),4.51 (q, J = 6.7 Hz, 2H), 2.15 (s, dihydropteridin-5(6H)- 8H), 1.50 (d,J = 6.8 Hz, 3H). MS (ES⁺): m/z = yl]benzonitrile 516.32 [MH⁺]. UPLC:t_(R) = 0.85 min (TOF: polar_2 min). 269 4-{[(7R)-5-(3-cyanophenyl)-8-¹H NMR (400 MHz, CD₃OD): δ 7.84-7.95 (m, (4,4-difluorocyclohexyl)-7-3H), 7.71-7.81 (m, 4H), 7.65 (d, J = 8.3 Hz, 1H), methyl-6-oxo-5,6,7,8-7.15 (br. s., 1H), 4.46-4.60 (m, 2H), 2.16-2.34 tetrahydropteridin-2-(m, 4H), 1.90-2.12 (m, 4H), 1.49 (d, J = 6.8 Hz, yl]amino}benzoic acid3H). MS (ES⁺): m/z = 519.34 [MH⁺]. UPLC: t_(R) = 1.00 min (TOF: polar_2min). 270 3-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ 8.67 (d, J = 2.3difluorocyclohexyl)-7-methyl-6- Hz, 1H), 8.45 (d, J = 2.5 Hz, 1H), 8.02(s, 1H), oxo-2-(1H-pyrazolo[3,4- 7.84-7.91 (m, 1H), 7.72-7.81 (m, 2H),7.65 (d, b]pyridin-5-ylamino)-7,8- J = 8.1 Hz, 1H), 7.09 (s, 1H), 4.48(q, J = 6.7 Hz, dihydropteridin-5(6H)- 2H), 2.10-2.25 (m, 4H), 1.84-2.07(m, 4H), 1.48 yl]benzonitrile (d, J = 6.8 Hz, 3H). MS (ES⁺): m/z =516.16 [MH⁺]. UPLC: t_(R) = 0.81 min (TOF: polar_2 min). 2714-{[(7R)-5-(3-cyanophenyl)-8- ¹H NMR (400 MHz, CD₃OD): δ 7.86-7.94 (m,(4,4-difluorocyclohexyl)-7- 2H), 7.72-7.85 (m, 3H), 7.66 (d, J = 7.8 Hz,1H), methyl-6-oxo-5,6,7,8- 7.14-7.36 (m, 2H), 4.62 (t, J = 11.7 Hz, 1H),tetrahydropteridin-2-yl]amino}- 4.52 (q, J = 6.8 Hz, 1H), 2.20-2.38 (m,3H), 2-fluorobenzoic acid 1.90-2.19 (m, 5H), 1.46-1.55 (m, 3H). MS(ES⁺): m/z = 537.30 [MH⁺]. UPLC: t_(R) = 1.09 min (TOF: polar_2 min).272 4-{[(7R)-5-(3-cyanophenyl)-8- ¹H NMR (400 MHz, CD₃OD): δ 7.85-7.96(m, (4,4-difluorocyclohexyl)-7- 2H), 7.71-7.83 (m, 3H), 7.61-7.68 (m,1H), 7.33 methyl-6-oxo-5,6,7,8- (dd, J = 1.8, 8.6 Hz, 1H), 7.18 (s, 1H),4.62 (t, tetrahydropteridin-2-yl]amino}- J = 11.7 Hz, 1H), 4.52 (q, J =6.7 Hz, 1H), 1.87- 2-fluorobenzamide 2.36 (m, 8H), 1.50 (d, J = 6.8 Hz,3H). MS (ES⁺): m/z = 536.02 [MH⁺]. UPLC: t_(R) = 1.02 min (TOF: polar_2min). 273 4-{[(7R)-5-(3-cyanophenyl)-8- ¹H NMR (400 MHz, CD₃OD): δ7.85-7.90 (m, (4,4-difluorocyclohexyl)-7- 1H), 7.72-7.84 (m, 6H), 7.65(d, J = 8.1 Hz, 1H), methyl-6-oxo-5,6,7,8- 7.13-7.17 (m, 1H), 4.46-4.61(m, 2H), 1.90-2.34 tetrahydropteridin-2- (m, 8H), 1.49 (d, J = 6.8 Hz,3H). MS (ES⁺): m/z = yl]amino}benzenesulfonamide 554.28 [MH⁺]. UPLC:t_(R) = 0.97 min (TOF: polar_2 min). 274 3-[(7R)-2-[(4- ¹H NMR (400 MHz,CD₃OD): δ 7.72-7.90 (m, cyanophenyl)amino]-8-(4,4- 5H), 7.65 (d, J = 8.1Hz, 1H), 7.55-7.60 (m, 2H), difluorocyclohexyl)-7-methyl- 7.16 (s, 1H),4.51 (q, J = 6.7 Hz, 2H), 1.89-2.32 6-oxo-7,8-dihydropteridin- (m, 8H),1.49 (d, J = 6.8 Hz, 3H). MS (ES⁺): m/z = 5(6H)-yl]benzonitrile 500.33[MH⁺]. UPLC: t_(R) = 1.23 min (TOF: polar_2 min). 2753-[(7R)-2-{[4-amino-3- ¹H NMR (400 MHz, CD₃OD): δ 7.82-7.89 (m,(trifluoromethyl)phenyl]amino}- 1H), 7.70-7.79 (m, 2H), 7.59-7.66 (m,2H), 7.39 8-(4,4-difluorocyclohexyl)-7- (dd, J = 2.1, 9.0 Hz, 1H), 7.04(s, 1H), 6.82 (d, methyl-6-oxo-7,8- J = 8.6 Hz, 1H), 4.38-4.58 (m, 2H),1.81-2.26 (m, dihydropteridin-5(6H)- 8H), 1.46 (d, J = 6.8 Hz, 3H). MS(ES⁺): m/z = yl]benzonitrile 558.31 [MH⁺]. UPLC: t_(R) = 1.01 min (TOF:polar_2 min). 276 3-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ 7.86 (dd, J= 1.0, difluorocyclohexyl)-2-[(3,5- 7.8 Hz, 1H), 7.71-7.79 (m, 2H), 7.63(d, J = 8.1 difluoro-4-hydroxyphenyl) Hz, 1H), 7.20-7.31 (m, 2H), 7.08(s, 1H), 4.57 (t, amino]-7-methyl-6-oxo-7,8- J = 11.9 Hz, 1H), 4.49 (q,J = 6.8 Hz, 1H), 2.18- dihydropteridin-5(6H)- 2.33 (m, 3H), 2.04-2.16(m, 2H), 1.98-2.01 (m, yl]benzonitrile 1H), 1.86-1.95 (m, 2H), 1.48 (d,J = 6.6 Hz, 3H). MS (ES⁺): m/z = 527.58 [MH⁺]. UPLC: t_(R) = 1.00 min(TOF: polar_2 min). 277 3-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ1.45-1.52 (m, difluorocyclohexyl)-2-[(4- 3H), 1.80-2.36 (m, 8H),4.45-4.58 (m, 2H), 7.10 fluoro-2-oxo-2,3-dihydro-1,3- (s, 1H), 7.36 (dd,J = 12.5, 1.6 Hz, 1H), 7.44 (s, benzoxazol-6-yl)amino]-7- 1H), 7.65 (d,J = 7.8 Hz, 1H), 7.75 (t, J = 7.9 Hz, methyl-6-oxo-7,8- 1H), 7.79 (s,1H), 7.83-7.90 (m, 1H). MS(ES⁺): dihydropteridin-5(6H)- m/z = 550.61[MH⁺]. HPLC: t_(R) = 0.98 min yl]benzonitrile (analytical_2min, UPLC).278 5-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ 1.44 (dd, J = 5.9,difluorocyclohexyl)-2-[(4- 1.6 Hz, 6H), 1.46-1.53 (m, 3H), 1.78-2.18 (m,fluoro-2-oxo-2,3-dihydro-1,3- 6H), 2.19-2.32 (m, 2H), 2.33-2.41 (m, 1H),4.41- benzoxazol-6-yl)amino]-7- 4.61 (m, 2H), 7.06-7.24 (m, 1H), 7.31(d, J = 8.8 methyl-6-oxo-7,8- Hz, 1H), 7.37 (d, J = 12.3 Hz, 1H),7.42-7.53 (m, dihydropteridin-5(6H)-yl]-2- 2H), 7.56 (br. s., 1H).MS(ES⁺): m/z = (propan-2-yloxy)benzonitrile 608.44[MH⁺]. HPLC: t_(R) =1.16 min (analytical_2 min, UPLC). 279 5-[(7R)-8-(4,4- ¹H NMR (400 MHz,CD₃OD): δ 1.47 (d, J = 6.5 difluorocyclohexyl)-7-methyl-6- Hz, 3H),1.72-2.04 (m, 4H), 2.08-2.31 (m, 4H), oxo-2-(1H-pyrazolo[3,4- 4.03 (s,3H), 4.38-4.53 (m, 2H), 7.11 (s, 1H), b]pyridin-5-ylamino)-7,8- 7.36 (d,J = 9.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, dihydropteridin-5(6H)-yl]-2- 1H),7.65 (s, 1H), 8.02 (s, 1H), 8.44 (d, J = 1.7 methoxybenzonitrile Hz,1H), 8.66 (s, 1H). MS(ES⁺): m/z = 546.15[MH⁺]. HPLC: t_(R) = 0.89 min(analytical_2 min, UPLC). 280 5-[(7R)-8-(4,4- 1H NMR (400 MHz, CD₃OD): δ1.45-1.54 (m, difluorocyclohexyl)-2-[(4- 6H), 1.84-2.39 (m, 8H), 4.27(q, J = 6.9 Hz, 2H), fluoro-2-oxo-2,3-dihydro-1,3- 4.47 (q, J = 6.8 Hz,1H), 4.56 (t, J = 11.4 Hz, benzoxazol-6-yl)amino]-7- 1H), 7.16 (br. s.,1H), 7.30 (d, J = 9.0 Hz, 1H), methyl-6-oxo-7,8- 7.37 (dd, J = 12.5, 1.6Hz, 1H), 7.45 (s, 1H), 7.51 dihydropteridin-5(6H)-yl]-2- (d, J = 8.8 Hz,1H), 7.58 (br. s., 1H). MS(ES⁺): ethoxybenzonitrile m/z = 594.38 [MH⁺].HPLC: t_(R) = 1.09 (analytical_2 min, UPLC). 281 5-[(7R)-8-(4,4-MS(ES⁺): m/z = 580.36[MH⁺]. HPLC: t_(R) = 1.02difluorocyclohexyl)-2-[(4- min (analytical_2 min, UPLC).fluoro-2-oxo-2,3-dihydro-1,3- benzoxazol-6-yl)amino]-7-methyl-6-oxo-7,8- dihydropteridin-5(6H)-yl]-2- methoxybenzonitrile 2825-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ 1.41-1.61 (m,difluorocyclohexyl)-7-methyl-6- 6H), 1.78-2.03 (m, 4H), 2.10-2.25 (m,4H), oxo-2-(1H-pyrazolo[3,4- 4.28 (q, J = 6.9 Hz, 2H), 4.38-4.53 (m,2H), 7.12 b]pyridin-5-ylamino)-7,8- (s, 1H), 7.28-7.43 (m, 1H),7.46-7.60 (m, 1H), dihydropteridin-5(6H)-yl]-2- 7.65 (d, J = 2.2 Hz,1H), 8.02 (s, 1H), 8.32-8.49 ethoxybenzonitrile (m, 1H), 8.67 (d, J =2.02 Hz, 1H). MS(ES⁺): m/z = 560.40[MH⁺]. HPLC: t_(R) = 0.97 min(analytical_2 min, UPLC). 283 5-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ1.44-1.54 (m, difluorocyclohexyl)-7-methyl-6- 3H), 1.80-2.37 (m, 8H),4.02 (d, J = 1.0 Hz, 3H), oxo-2-[(2-oxo-2,3-dihydro-1,3- 4.39-4.57 (m,2H), 6.86-7.02 (m, 1H), 7.16 (d, benzoxazol-6-yl)amino]-7,8- J = 8.5 Hz,2H), 7.30 (d, J = 8.8 Hz, 1H), 7.46- dihydropteridin-5(6H)-yl]-2- 7.61(m, 2H), 7.71-7.80 (m, 1H). MS(ES⁺): m/z = methoxybenzonitrile562.31[MH⁺]. HPLC: t_(R) = 0.87 min (analytical_2 min, UPLC). 2845-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ 1.43-1.54 (m,difluorocyclohexyl)-7-methyl-6- 6H), 1.79-2.37 (m, 8H), 4.26 (q, J = 6.8Hz, 2H), oxo-2-[(2-oxo-2,3-dihydro-1,3- 4.40-4.54 (m, 2H), 6.96 (d, J =8.3 Hz, 1H), 7.17 benzoxazol-6-yl)amino]-7,8- (d, J = 8.0 Hz, 2H), 7.28(d, J = 8.8 Hz, 1H), dihydropteridin-5(6H)-yl]-2- 7.49 (d, J = 8.5 Hz,1H), 7.56 (br. s., 1H), 7.75 ethoxybenzonitrile (d, J = 1.7 Hz, 1H).MS(ES⁺): m/z = 576.35[MH⁺]. HPLC: t_(R) = 0.93 min (analytical_2 min,UPLC). 285 5-[(7R)-8-(4,4- ¹H NMR (400 MHz, CD₃OD): δ 1.43 (d, J = 6.0difluorocyclohexyl)-7-methyl-6- Hz, 6H), 1.47 (d, J = 6.8 Hz, 3H),1.77-2.33 (m, oxo-2-[(2-oxo-2,3-dihydro-1,3- 8H), 4.39-4.56 (m, 2H),4.81 (d, J = 6.0 Hz, 1H), benzoxazol-6-yl)amino]-7,8- 6.96 (d, J = 8.5Hz, 1H), 7.17 (d, J = 8.3 Hz, dihydropteridin-5(6H)-yl]-2- 2H), 7.28 (d,J = 9.0 Hz, 1H), 7.47 (d, J = 8.3 (propan-2-yloxy)benzonitrile Hz, 1H),7.54 (br. s., 1H), 7.76 (s, 1H). MS(ES⁺): m/z = 590.36[MH⁺]. HPLC: t_(R)= 0.98 min (analytical_2 min, UPLC). 286 5-[(7R)-8-(4,4- ¹H NMR (400MHz, CD₃OD): δ 1.44 (d, J = 6.0, difluorocyclohexyl)-7-methyl-6- 6H),1.47 (d, J = 6.8, 3H), 1.79-2.28 (m, 8H), oxo-2-(1H-pyrazolo[3,4-4.30-4.50 (m, 2H), 4.78 (t, J = 5.6 Hz, 1H), 7.15b]pyridin-5-ylamino)-7,8- (br. s., 1H), 7.24 (d, J = 8.3 Hz, 1H),7.40-7.55 dihydropteridin-5(6H)-yl]-2- (m, 2H), 7.97 (s, 1H), 8.40 (s,1H), 8.65 (br. s., (propan-2-yloxy)benzonitrile 1H). MS(ES⁺): m/z =574.31[MH⁺]. HPLC: t_(R) = 0.95 min (analytical_2 min, UPLC).

Examples 287-295 were prepared according to procedures similar to thepreparation of Example 18, using corresponding starting materials andintermediates. For example, for the synthesis of example 287, methyl(2R)-2-aminobutanoate hydrochloride and cyclohexanone were used in thestep a of the synthesis, (3-cyanophenyl)boronic acid was used in thestep d of the synthesis and 7-fluoro-1H-indazol-5-amine was used in thestep e of the synthesis.

Examples 296 were prepared according to procedures similar for thepreparation of Example 18, using corresponding starting materials andintermediates. More specifically, methyl (2R)-2-aminobutanoatehydrochloride and cyclopentanone were used in the step a of thesynthesis, (3-cyanophenyl)boronic acid was used in the step d of thesynthesis and 1H-indazol-5-amine was used in the step e of thesynthesis.

Ex. # Chemical Name Analytical data 287 3-[(7R)-8-cyclohexyl-7-ethyl-2-1H NMR (400 MHz, CD₃OD) δ 7.98 (d, J = 3.0 [(7-fluoro-1H-indazol-5- Hz,1H), 7.87 (d, J = 7.8 Hz, 1H), 7.74-7.79 (m, yl)amino]-6-oxo-7,8- 3H),7.63 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 12.4 dihydropteridin-5(6H)- Hz,1H), 7.01 (s, 1H), 4.38 (dd, J = 4.5, 7.6 Hz, yl]benzonitrile 2H), 2.22(d, J = 11.9 Hz, 1H), 1.79-1.98 (m, 6H), 1.57-1.77 (m, 2H), 1.48 (q, J =12.5 Hz, 2H), 1.24 (d, J = 13.1 Hz, 1H), 1.03 (t, J = 7.5 Hz, 3H). MS(ES⁺): m/z = 511.44 [M + H]⁺. UPLC: t_(R) = 0.98 min (TOF: polar_2 min).288 (7R)-8-cyclohexyl-7-ethyl-2-[(7- ¹H NMR (400 MHz, CD₃OD): δ 8.68(dd, J = 1.0, fluoro-1H-indazol-5-yl)amino]-5- 4.8 Hz, 1H), 8.53 (d, J =2.3 Hz, 1H), 8.00 (d, J = (pyridin-3-yl)-7,8- 2.8 Hz, 1H), 7.85 (d, J =8.3 Hz, 1H), 7.79 (d, J = dihydropteridin-6(5H)-one 1.5 Hz, 1H), 7.66(dd, J = 5.1, 8.1 Hz, 1H), 7.48 (d, J = 12.9 Hz, 1H), 7.04 (s, 1H), 4.41(dd, J = 4.5, 7.6 Hz, 2H), 2.23 (d, J = 11.4 Hz, 1H), 1.82- 2.00 (m,6H), 1.59-1.78 (m, 2H), 1.50 (q, J = 13.1 Hz, 2H), 1.21-1.32 (m, 1H),1.04 (t, J = 7.6 Hz, 3H). MS (ES⁺): m/z = 487.36 [MH⁺]. UPLC: t_(R) =0.85 min (TOF: polar_2 min). 289 (7R)-8-cyclohexyl-5-(3,4- ¹H NMR (400MHz, CD₃OD): δ 7.99 (d, J = 3.3 dimethoxyphenyl)-7-ethyl-2-[(7- Hz, 1H),7.78 (d, J = 1.5 Hz, 1H), 7.47 (d, J = fluoro-1H-indazol-5-yl)amino]-12.4 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.03 (s,7,8-dihydropteridin-6(5H)-one. 1H), 6.80-6.88 (m, 2H), 4.39 (dd, J =3.9, 8.0 Hz, 2H), 3.91 (s, 3H), 3.80-3.86 (m, 3H), 2.23 (d, J = 12.1 Hz,1H), 1.82-1.99 (m, 6H), 1.60-1.77 (m, 3H), 1.41-1.53 (m, 2H), 1.03 (t, J= 7.6 Hz, 3H). MS (ES⁺): m/z = 546.40 [MH⁺]. UPLC: t_(R) = 0.94 min(TOF: polar_2 min). 290 (7R)-8-cyclohexyl-7-ethyl-2-[(7- ¹H NMR (400MHz, CD₃OD): δ 7.98 (d, J = 3.3 fluoro-1H-indazol-5-yl)amino]-5- Hz,1H), 7.78 (d, J = 1.5 Hz, 1H), 7.56-7.64 (m, (3-fluorophenyl)-7,8- 1H),7.47 (d, J = 13.4 Hz, 1H), 7.24-7.31 (m, 1H), dihydropteridin-6(5H)-one7.09-7.15 (m, 2H), 7.02 (s, 1H), 4.34-4.45 (m, 2H), 2.22 (d, J = 10.6Hz, 1H), 1.80-2.00 (m, 6H), 1.58-1.76 (m, 2H), 1.40-1.55 (m, 2H),1.19-1.30 (m, 1H), 1.02 (t, J = 7.6 Hz, 3H). MS (ES⁺): m/z =504.40[MH⁺]. UPLC: t_(R) = 1.00 min (TOF: polar_2 min). 291(7R)-8-cyclohexyl-7-ethyl-2-[(7- ¹H NMR (400 MHz, CD₃OD): δ 7.99 (d, J =3.0 fluoro-1H-indazol-5-yl)amino]-5- Hz, 1H), 7.76-7.86 (m, 3H),7.61-7.65 (m, 1H), [3-(trifluoromethyl)phenyl]-7,8- 7.58 (d, J = 7.6 Hz,1H), 7.47 (d, J = 12.6 Hz, dihydropteridin-6(5H)-one. 1H), 6.98 (s, 1H),4.36-4.46 (m, 2H), 2.23 (d, J = 11.6 Hz, 1H), 1.82-2.00 (m, 6H),1.59-1.76 (m, 2H), 1.40-1.55 (m, 2H), 1.31-1.38 (m, 1H), 1.04 (t, J =7.5 Hz, 3H). MS (ES⁺): m/z = 554.36 [MH⁺]. UPLC: t_(R) = 1.11 min (TOF:polar_2 min). 292 (7R)-8-cyclohexyl-7-ethyl-2-[(7- ¹H NMR (400 MHz,CD₃OD): δ 7.99 (br. s., 2H), fluoro-1H-indazol-5-yl)amino]-5- 7.77 (d, J= 1.3 Hz, 1H), 7.42-7.50 (m, 2H), 7.08 [6-(morpholin-4-yl)pyridin-3-yl]-(s, 1H), 6.96 (d, J = 9.1 Hz, 1H), 4.38 (dd, J =7,8-dihydropteridin-6(5H)-one 4.2, 8.0 Hz, 2H), 3.77-3.84 (m, 4H),3.55-3.60 (m, 4H), 2.22 (d, J = 9.3 Hz, 1H), 1.80-1.96 (m, 6H),1.61-1.76 (m, 2H), 1.41-1.52 (m, 2H), 1.35 (br. s., 1H), 1.00 (t, J =7.5 Hz, 3H). MS (ES⁺): m/z = 572.57[MH⁺]. UPLC: t_(R) = 0.93 min (TOF:polar_2 min). 293 (7R)-8-cyclohexyl-5-[6- ¹H NMR (400 MHz, CD₃OD): δ7.89-7.94 (m, (dimethylamino)pyridin-3-yl]-7- 1H), 7.74-7.80 (m, 2H),7.61-7.66 (m, 1H), 7.01 ethyl-2-[(7-fluoro-1H-indazol-5- (s, 1H),4.87-5.00 (m, 1H), 4.70-4.83 (m, 1H), yl)amino]-7,8-dihydropteridin-4.31 (quin, J = 8.4 Hz, 1H), 2.08-2.19 (m, 2H), 6(5H)-one 1.97-2.07 (m,4H), 1.61-1.76 (m, 2H). MS (ES⁺): m/z = 530.47 [MH⁺]. UPLC: t_(R) = 0.86min (TOF: polar_2 min). 294 (7R)-8-cyclohexyl-7-ethyl-2-[(7- ¹H NMR (400MHz, CD₃OD): δ 7.98 (d, J = 3.3 fluoro-1H-indazol-5-yl)amino]-5- Hz,1H), 7.77 (d, J = 1.5 Hz, 1H), 7.46 (d, J = (3-fluoro-4-methoxyphenyl)-12.9 Hz, 1H), 7.28 (t, J = 9.0 Hz, 1H), 6.99-7.127,8-dihydropteridin-6(5H)-one (m, 3H), 4.37 (dd, J = 3.9, 8.0 Hz, 2H),3.95 (s, 3H), 2.22 (d, J = 11.9 Hz, 1H), 1.80-1.97 (m, 6H), 1.58-1.77(m, 2H), 1.48 (q, J = 12.6 Hz, 2H), 1.23 (d, J = 13.4 Hz, 1H), 1.01 (t,J = 7.5 Hz, 3H). MS (ES⁺): m/z = 534.44 [MH⁺]. UPLC: t_(R) = 1.00 min(TOF: polar_2 min). 295 3-[(7R)-8-cyclohexyl-7-ethyl-2- ¹H NMR (400 MHz,CD₃OD): δ 8.08 (d, J = 1.3 [(3-fluoro-1H-indazol-5- Hz, 1H), 7.85-7.90(m, 1H), 7.73-7.78 (m, 2H), yl)amino]-6-oxo-7,8- 7.63 (d, J = 8.6 Hz,1H), 7.44-7.49 (m, 1H), 7.35 dihydropteridin-5(6H)- (dd, J = 1.8, 9.1Hz, 1H), 7.02 (s, 1H), 4.40-4.50 yl]benzonitrile (m, 1H), 4.38 (dd, J =4.9, 7.5 Hz, 1H), 2.19 (d, J = 10.4 Hz, 1H), 1.80-1.98 (m, 6H),1.59-1.75 (m, 2H), 1.42-1.56 (m, 2H), 1.20-1.30 (m, 1H), 1.03 (t, J =7.6 Hz, 3H). MS (ES⁺): m/z = 511.47 [MH⁺]. UPLC: t_(R) = 1.01 min (TOF:polar_2 min). 296 3-[(7R)-8-cyclopentyl-7-ethyl-2- ¹H NMR (400 MHz,CD₃OD): δ 8.08 (d, J = 1.0 (1H-indazol-5-ylamino)-6-oxo- Hz, 1H), 7.93(td, J = 1.3, 7.8 Hz, 1H), 7.80-7.84 7,8-dihydropteridin-5(6H)- (m, 2H),7.76-7.80 (m, 1H), 7.66-7.72 (m, 1H), yl]benzonitrile 7.63 (d, J = 8.8Hz, 1H), 7.37 (dd, J = 1.8, 8.8 Hz, 1H), 6.67 (s, 1H), 4.56 (dd, J =3.5, 6.8 Hz, 1H), 4.21 (t, J = 8.8 Hz, 1H), 1.84-2.17 (m, 6H), 1.45 (br.s., 4H), 1.03 (t, J = 7.5 Hz, 3H). MS (ES⁺): m/z = 479.48 [MH⁺]. UPLC:t_(R) = 0.89 min (TOF: polar_2 min).

Examples 297-299 were prepared according to procedures similar to thepreparation of Example 18, using corresponding starting materials andintermediates. For example, for the synthesis of example 297,spiro[2.5]octan-6-one and D-alanine methyl ester hydrochloride were usedin the step a of the synthesis, (3-cyanophenyl)boronic acid was used inthe step d of the synthesis and 7-fluoro-1H-indazol-5-amine was used inthe step e of the synthesis.

Ex. # Chemical Name Analytical data 2973-[(7R)-2-[(7-fluoro-1H-indazol-5- ¹H NMR (400 MHz, CD₃OD): δ 7.99 (br.s., yl)amino]-7-methyl-6-oxo-8- 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.71-7.81(m, (spiro[2.5]oct-6-yl)-7,8- 3H), 7.65 (d, J = 8.6 Hz, 1H), 7.50 (d, J= 13.6 dihydropteridin-5(6H)- Hz, 1H), 7.08 (s, 1H), 4.49-4.63 (m, 2H),2.19 yl]benzonitrile (d, J = 10.9 Hz, 1H), 1.93-2.08 (m, 3H), 1.73- 1.84(m, 2H), 1.50 (d, J = 6.6 Hz, 3H), 1.00- 1.10 (m, 2H), 0.28-0.41 (m,4H). MS (ES⁺): m/z = 523.29 [MH⁺]. UPLC: t_(R) = 1.00 min (TOF: polar_2min). 298 (7R)-2-[(7-fluoro-1H-indazol-5- ¹H NMR (400 MHz, CD₃OD): δ8.67 (d, J = 3.5 yl)amino]-7-methyl-5-(pyridin-3- Hz, 1H), 8.54 (d, J =2.5 Hz, 1H), 7.98 (d, J = yl)-8-(spiro[2.5]oct-6-yl)-7,8- 3.0 Hz, 1H),7.86 (d, J = 8.8 Hz, 1H), 7.80 (d, dihydropteridin-6(5H)-one. J = 1.0Hz, 1H), 7.65 (dd, J = 4.8, 8.1 Hz, 1H), 7.51 (d, J = 13.9 Hz, 1H), 7.10(s, 1H), 4.49- 4.64 (m, 2H), 2.18 (br. s., 1H), 2.01 (q, J = 13.6 Hz,3H), 1.74-1.87 (m, 2H), 1.52 (d, J = 6.8 Hz, 3H), 1.06 (br. s., 2H),0.28-0.43 (m, 4H). MS (ES⁺): m/z = 499.14 [MH⁺]. UPLC: t_(R) = 0.88 min(TOF: polar_2 min). 299 (7R)-5-(3,4-dimethoxyphenyl)-2- ¹H NMR (400 MHz,CD₃OD): δ 7.98 (d, J = 2.3 [(7-fluoro-1H-indazol-5-yl)amino]- Hz, 1H),7.79 (d, J = 1.5 Hz, 1H), 7.49 (d, J = 7-methyl-8-(spiro[2.5]oct-6-yl)-12.6 Hz, 1H), 7.06-7.15 (m, 2H), 6.86 (br. s.,7,8-dihydropteridin-6(5H)-one 2H), 4.45-4.61 (m, 2H), 3.90 (s, 3H), 3.83(s, 3H), 2.19 (d, J = 11.6 Hz, 1H), 1.95-2.08 (m, 2H), 1.69-1.83 (m,1H), 1.50 (d, J = 6.8 Hz, 4H), 0.98-1.12 (m, 3H), 0.27-0.41 (m, 4H). MS(ES⁺): m/z = 558.04 [MH⁺]. UPLC: t_(R) = 0.96 min (TOF: polar_2 min).

Examples 300-302 were prepared according to procedures similar to thepreparation of Example 18, using corresponding starting materials andintermediates. For example, for the synthesis of example 302,(²H₁₀)cyclohexanone and D-alanine methyl ester hydrochloride were usedin the step a of the synthesis, (3-cyanophenyl)boronic acid was used inthe step d of the synthesis, 7-fluoro-1H-indazol-5-amine was used in thestep e of the synthesis.

Ex. # Chemical Name Analytical data 300 (7R)-8-[(2,2,3,3,4,4,5,5,6,6- ¹HNMR (400 MHz, CD₃OD): δ 1.48 (d, J = 6.8 ²H₁₀)cyclohexyl]-5-(3,4- Hz,3H), 3.84 (s, 3H), 3.91 (s, 3H), 4.40-4.53 (m,dimethoxyphenyl)-2-[(7-fluoro- 2H), 6.87 (br. s., 2H), 7.09 (s, 1H),7.12 (d, J = 1H-indazol-5-yl)amino]-7-methyl- 8.5 Hz, 1H), 7.49 (d, J =13.3 Hz, 1H), 7.79 (d, 7,8-dihydropteridin-6(5H)-one J = 1.5 Hz, 1H),7.99 (d, J = 3.0 Hz, 1H). MS(ES⁺): m/z = 542.12 [MH⁺]. HPLC: t_(R) =0.86 min (analytical_2 min, UPLC). 301 (7R)-8-[(2,2,3,3,4,4,5,5,6,6- ¹HNMR (400 MHz, CD₃OD): δ 1.51 (d, J = 6.8²H₁₀)cyclohexyl]-2-[(7-fluoro-1H- Hz, 3H), 4.45 (s, 1H), 4.48-4.55 (m,1H), 7.10 (s, indazol-5-yl)amino]-7-methyl-5- 1H), 7.48 (d, J = 12.6 Hz,1H), 7.64 (dd, J = 8.0, (pyridin-3-yl)-7,8-dihydropteridin- 4.8 Hz, 1H),7.78 (dd, J = 1.7, 1.0 Hz, 1H), 7.82 6(5H)-one (d, J = 8.0 Hz, 1H), 7.96(d, J = 3.0 Hz, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.66 (dd, J = 4.9, 1.1Hz, 1H). MS(ES⁺): m/z = 483.25 [MH⁺]. HPLC: t_(R) = 0.78 min(analytical_2 min, UPLC). 302 3-[(7R)-8-[(2,2,3,3,4,4,5,5,6,6- ¹H NMR(400 MHz, CD₃OD): δ 1.49 (d, J = 6.8 ²H₁₀)cyclohexyl]-2-[(7-fluoro-1H-Hz, 3H), 4.43 (s, 1H), 4.50 (d, J = 6.8 Hz, 1H),indazol-5-yl)amino]-7-methyl-6- 7.06 (br. s., 1H), 7.49 (d, J = 13.1 Hz,1H), 7.64 oxo-7,8-dihydropteridin-5(6H)- (d, J = 8.0 Hz, 1H), 7.75 (t, J= 7.9 Hz, 1H), 7.79 yl]benzonitrile (d, J = 1.5 Hz, 2H), 7.87 (dt, J =7.8, 1.2 Hz, 1H), 7.99 (d, J = 3.0 Hz, 1H). MS(ES⁺): m/z = 507.30[MH⁺].HPLC: t_(R) = 0.90 min (analytical_2 min, UPLC). 303(7R)-8-cyclohexyl-2-[(7-fluoro- ¹H NMR (DMSO-d₆, 400 MHz): δ 13.41 (brs,1H-indazol-5-yl)amino]-7-methyl- exchanges with D₂O, 1H), 9.32 (s,exchanges 5-(1-oxidopyridin-3-yl)-7,8- with D₂O, 1H), 8.44 (dd, J = 1.6,1.6 Hz, 1H), dihydropteridin-6(5H)-one 8.32 (ddd, J = 6.4, 1.6, 1.2 Hz,1H), 8.01 (brs, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.61-7.55 (m, 2H), 7.40(dd, J = 8.2, 0.6 Hz, 1H), 7.33 (s, 1H), 4.46 (q, J = 6.8 Hz, 1H), 4.38(tt, J = 12.0, 3.6 Hz, 1H), 1.96-1.51 (m, 6H), 1.50-1.39 (m, 2H), 1.38(d, J = 6.8 Hz, 3H), 1.29-1.20 (m, 2H). MS(ES⁺): m/z = 489.37 [MH⁺].HPLC: t_(R) = 0.78 min (analytical_2 min, UPLC). 304(7R)-8-(4,4-dimethylcyclohexyl)- ¹H NMR (CD₃OD, 400 MHz): δ 0.94 (s, 3H), 0.96 2-[(7-fluoro-1H-indazol-5- (s, 3 H), 1.31 (t, J = 11.2 Hz, 1H), 1.41-1.56 (m, yl)amino]-7-methyl-5-(1- 3 H), 1.44 (d, J = 6.8 Hz, 3H), 1.67 (m, 1 H), oxidopyridin-3-yl)-7,8- 1.90-1.98 (m, 2 H), 2.61 (m,1 H), 4.32 (t, J = dihydropteridin-6(5H)-one 12.0 Hz, 1 H), 4.51 (q, J =6.8 Hz, 1 H), 7.26 (s, 1 H), 7.47 (d, J = 13.2 Hz, 1 H), 7.60-7.68 (m, 2H), 7.81 (d, J = 1.6 Hz, 1 H), 7.95 (d, J = 3.2 Hz, 1 H), 8.41 (d, J =6.4 Hz, 1 H), 8.58 (t, J = 1.6 Hz, 1 H). MS (ES⁺): m/z = 517.63 [MH⁺].HPLC: t_(R) = 0.83 min (TOF, polar_2 min).

Example 303 was prepared by the following procedure:

Step c:(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(1-oxidopyridin-3-yl)-7,8-dihydropteridin-6(5H)-one

To a solution of(7R)-2-chloro-8-cyclohexyl-7-methyl-5-(1-oxidopyridin-3-yl)-7,8-dihydropteridin-6(5H)-one(30.4 mg, 0.081 mmol) and 7-fluoro-1H-indazol-5-amine (37.2 mg, 0.25mmol) in trifluoroethanol (2.0 mL, 27 mmol) in a microwave reactor vialwas added trifluoroacetic acid (42 mg, 0.37 mmol). The vial was thensealed, and the mixture was stirred at 100° C. (oil bath). More7-fluoro-1H-indazol-5-amine (29.5 mg, 0.195 mmol) and trifluoroaceticacid (0.025 mL, 0.32 mmol) was added after 15 h, and heating at 100° C.was continued for additional 24 h. The reaction mixture was cooled to rtand quenched with saturated aq. NaHCO₃ solution (5 mL). The resultingmixture was extracted with 5% MeOH in dichloromethane (15 mL×4). Thecombined organic layers were washed with water and brine, dried overNa₂SO₄, filtered, and concentrated in vacuo to give a crude residue,which was then purified by silica gel column chromatography (eluent: 8%methanol in dichloromethane) to give the desired product (24%).

Step b: Synthesis of(7R)-2-chloro-8-cyclohexyl-7-methyl-5-(1-oxidopyridin-3-yl)-7,8-dihydropteridin-6(5H)-one

To a stirred solution of(7R)-2-chloro-8-cyclohexyl-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one(51.2 mg, 0.143 mmol) in dichloromethane (2.5 mL) was added mCPBA (77%max, 33.7 mg, 0.150 mmol) at rt, and the solution was stirred at rt.More mCPBA (77% max, 10.2 mg, 0.0455 mmol) was added after 2.5 h, andstirring at rt was continued for additional 4 h. The reaction solutionwas diluted with dichloromethane (15 mL), washed with aq. NaHCO₃solution (20 mL×2), dried over Na₂SO₄, and concentrated in vacuo to givea crude residue, which was then purified by silica gel columnchromatography (eluent: 5% methanol in dichloromethane) to give thedesired product (0.116 mmol, 81% yield). ¹H NMR (CDCl₃, 400 MHz): δ 8.30(d, J=6.8 Hz, 1H), 8.17 (s, 1H), 7.45 (dd, J=8.4, 6.8 Hz, 1H), 7.33 (s,1H), 7.16 (d, J=8.4 Hz, 1H), 4.49 (q, J=6.8 Hz, 1H), 4.49-4.39 (m_(e),1H), 2.17-2.10 (m, 1H), 1.96-1.87 (m, 2H), 1.83-1.64 (m, 3H), 1.55-1.43(m, 3H), 1.47 (d, J=6.8 Hz, 3H), 1.25-1.14 (m, 1H). MS(ES⁺):m/z=374.13/376.21 [MH⁺].

Step a:(7R)-2-chloro-8-cyclohexyl-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-onewas prepared from(7R)-2-chloro-8-cyclohexyl-7-methyl-7,8-dihydropteridin-6(5H)-one andpyridin-3-ylboronic acid, according to procedures similar to step d forthe preparation of Example 18. Examples 304 was prepared according toprocedures similar to the preparation of Example 303, usingcorresponding starting materials and intermediates.

Ex. # Chemical Name Analytical data 305 2-(1H-indazol-5-ylamino)-8- ¹HNMR (DMSO-d₆, 400 MHz) δ 0.92 (d, J = 6.8 Hz,(3-methylbutyl)-5-phenyl-5,8- 6H), 1.56-1.73 (m, 3H), 4.21 (t, J = 7.2Hz, 2H), 7.35 dihydropteridine-6,7-dione (s, 1H), 7.39-7.42 (m, 3H),7.48-7.59 (m, 2H), 7.61 (t, J = 6.8 Hz, 2H), 7.87 (s, 1H), 8.10 (s, 1H),9.60 (s, 1H). MS(ES⁺): m/z = 442.06 [MH⁺]. HPLC: t_(R) = 2.72 (ZQ3,Polar_5 min). 306 8-(3-methylbutyl)-2-[(2-oxo- ¹H NMR (CDCl₃ and CD₃OD,300 MHz) δ 0.85 (d, J = 2,3-dihydro-1H-indol-5- 6.3 Hz, 6H), 1.51-1.56(m, 3H), 3.36 (s, 2H), 4.17-4.22 yl)amino]-5-phenyl-5,8- (m, 2H), 6.99(d, J = 8.1 Hz, 2H), 7.15-7.19 (m, 2H), dihydropteridine-6,7-dione7.22-7.25 (m, 1H), 7.33 (br. s, 1H), 7.42-7.50 (m, 4H). MS (ES⁺): m/z =456.96 (100) [MH⁺]. HPLC: t_(R) = 2.60 (ZQ3, Polar_5 min). 3078-cyclopentyl-2-(1H-indazol- ¹H NMR (CDCl₃ and CD₃OD, 400 MHz) δ1.79-1.85 5-ylamino)-5-phenyl-5,8- (m, 5H), 2.09-2.20 (m, 3H), 5.61-5.64(m, 1H), 7.19- dihydropteridine-6,7-dione 7.21 (m, 2H), 7.27-7.29 (m,1H), 7.36(d, J = 9.2 Hz, 1H), 7.44-7.51 (m, 4H), 7.82 (s, 1H), 7.87 (s,1H). MS(ES⁺): m/z = 440.04 [MH⁺]. HPLC: t_(R) = 2.55 (ZQ3, Polar_5 min).

Example 305 was prepared by the following procedures:

Step a: Synthesis of 2-chloro-N-(3-methylbutyl)-5-nitropyrimidin-4-amine

To a stirred solution of 2,4-dichloro-5-nitropyrimidine (13.8 g, 99.28mmol) and 3-methylbutan-1-amine (7.0 g, 80.45 mmol) in dichloroethane(150 mL) was added imidazole (3.78 g, 55.58 mmol) at 0° C., theresulting mixture was stirred at 0° C. for 30 minutes then stirred at rtfor 16 h. The solvent was removed under reduced pressure to give a cruderesidue was purified by silica gel column chromatography (eluent: 2%ethyl acetate in hexane) to yield 5.5 g of the desired compound. ¹H NMR(CDCl₃, 300 MHz) δ 0.98 (d, J=6.8 Hz, 6H), 1.56-1.81 (m, 3H), 3.60-3.75(m, 2H), 8.40 (br s, 1H), 9.01 (s, 1H); MS m/z 245[M+H+].

Step b: synthesis of 2-chloro-N⁴-(3-methylbutyl)pyrimidine-4,5-diamine

To a stirred solution of2-chloro-N-(3-methylbutyl)-5-nitropyrimidin-4-amine (800 mg, 3.27 mmol)in ethanol (40 ml) was added iron powder (1.8 g). The resulting mixturewas heated to reflux before 2 N aqueous hydrochloric acid (4 mL) wasadded in small portion over 10 min. The reaction was then refluxed for 2h. The reaction mixture was cooled to rt, filtered to remove inorganicmaterial. The solution was then concentrated under reduced pressure toafforded the desired compound (500 mg), which was used for next stepwithout any further purifications. ¹H NMR (CDCl₃, 300 MHz) δ 0.92 (d,J=6.8 Hz, 6H), 1.42-1.80 (m, 3H), 3.42-3.60 (m, 2H), 5.01-5.15 (br s1H), 7.60 (s, 1H).

Step c: Synthesis of2-chloro-8-(3-methylbutyl)-5,8-dihydropteridine-6,7-dione

To a stirred solution of2-chloro-N⁴-(3-methylbutyl)pyrimidine-4,5-diamine (2.8 g, 13.08 mmol) intoluene (40 mL) was added triethylamine (4.23 g, 41.88 mmol) and ethylchlorooxoacetate (1.95 g, 14.33). The mixture was then heated to refluxfor 16 h. It was then cooled to rt, the bulk of solvent was removedunder reduced pressure to give a crude residue, which was purified bysilica gel column chromatography (eluent: 70% ethyl acetate in hexane)afforded the desired product (2.1 g). ¹H NMR (CDCl₃, 300 MHz) δ 1.01 (d,J=6.6 Hz, 6H), 1.60-1.82 (m, 3H), 4.20-4.35 (m, 2H), 8.35 (s, 1H).

Step d: Synthesis of2-chloro-8-(3-methylbutyl)-5-phenyl-5,8-dihydropteridine-6,7-dione

To a stirred solution of2-chloro-8-(3-methylbutyl)-5,8-dihydropteridine-6,7-dione (500 mg, 1.86mmol), triethylamine (1.88 g, 18.61 mmol) in dichloromethane (20 mL) wasadded copper acetate (678 mg, 3.73 mmol), phenyl boronic acid (455 mg,3.73 mmol) and molecular sieves (4 Å, 2 g). The resulting mixture wasand stirred at rt for 60 h with an air balloon. The reaction mixture wasthen diluted with dichloromethane (20 mL) and filtered through celite toremove insoluble material. The bulk of solvent from filtration was thenremoved under reduced pressure to give a crude residue, which waspurified by a silica gel column chromatography (eluent: 40% ethylacetate in hexanes) to provided the desired compound (110 mg). ¹H NMR(CDCl₃, 300 MHz) δ 1.05 (d, J=6.8 Hz, 6H), 1.60-1.79 (m, 3H), 4.38-4.42(m, 2H), 7.21-7.38 (m, 3H), 7.48-7.65 (m, 2H), 7.79 (s, 1H).

Step e: Synthesis of2-(1H-indazol-5-ylamino)-8-(3-methylbutyl)-5-phenyl-5,8-dihydropteridine-6,7-dione

This compound was prepared from2-chloro-8-(3-methylbutyl)-5-phenyl-5,8-dihydropteridine-6,7-dione and5-aminoindazole, according to procedures similar to the preparation ofexample 18 from(7R)-2-chloro-8-cyclohexyl-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one.Examples 306 and 307 was prepared according to procedures similar forthe preparation of Example 305, using corresponding starting materialsand intermediates. For example, for synthesis of example 307,cyclopentanamine was used in the step a of the synthesis.

Ex. # Chemical Name Analytical data 308 (7R)-5-(3,4-dimethoxyphenyl)-2-¹H NMR (400 MHz, CD₃OD) δ 7.97-8.04 (m, [(7-fluoro-1H-indazol-5- 1H),7.70-7.83 (m, 1H), 7.40-7.52 (m, 1H), yl)amino]-7-methyl-8-(4- 7.08-7.15(m, 2H), 6.80-6.90 (m, 2H), 4.70- oxocyclohexyl)-7,8- 4.81 (m, 1H),4.41-4.54 (m, 1H), 3.90 (s, dihydropteridin-6(5H)-one 3H), 3.83 (s, 3H),2.53-2.70 (m, 1H), 2.39- 2.50 (m, 2H), 2.02-2.32 (m, 3H), 1.58-1.81 (m,2H), 1.45-1.53 (m, 3H). MS (ES⁺): m/z = 546.64 [MH⁺]. UPLC: t_(R) = 0.67min (TOF: polar_2 min). 309 3-[(7R)-8-(cis-4- MS (ES⁺): m/z = 495.38[MH⁺]. HPLC: t_(R) = hydroxycyclohexyl)-2-(1H- 0.71 min (TOF, polar_2min). indazol-5-ylamino)-7-methyl-6- oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile

Examples 308 and 309 were prepared according to procedures similar forthe preparation of Example 18, using corresponding starting materialsand intermediates.

Ex. # Chemical Name Analytical data 310 7-(1H-indazol-5-ylamino)-2- ¹HNMR (400 MHz, CD₃OD) δ 0.88 (d, J = 6.4 methyl-1-(3-methylbutyl)-4- Hz,3H), 0.95 (d, J = 6.4 Hz, 3H), 1.41 (d, J =phenyl-1,4-dihydropyrido[3,4- 6.82 Hz, 3 H), 1.55-1.65 (m, 3 H),3.18-3.28 b]pyrazin-3(2H)-one (m, 1 H), 3.39-3.49 (m, 1 H), 4.26 (q, J =6.74 Hz, 1 H), 6.10 (s, 1 H), 6.79 (s, 1 H), 7.27-7.34 (m, 3 H),7.49-7.55 (m, 2 H), 7.56-7.62 (m, 2 H), 7.75 (d, J = 1.52 Hz, 1 H),7.97(s, 1 H). MS(ES⁺): m/z 441.19 [MH⁺]. HPLC: t_(R) = 2.55(ZQ3, Polar_5min).

Example 310 was prepared according to the following procedures:

Step a: Synthesis of 2-bromo-N-(4,6-dichloropyridin-3-yl)propanamide

To a stirred mixture of 4,6-dichloro-pyridin-3-yl-amine dihydrochloride(1.50 g, 3.08 mmol) in a mixture of ether (6 mL) and ethyl acetate (5mL) at 0° C. was added a solution of potassium carbonate (426 mg, 3.0mmol) in water (4 mL), followed by 2-bromopropionoic acid chloride (2,0.34 mL) in drop wise over a period of 30 min. The reaction mixture wasthen stirred at rt for 45 min. The solids formed (desired product) wasfiltered and the solvent layer was extracted with ethyl acetate (20mL×3). The combined organic phases were dried over Na₂SO₄, evaporatedand to give a crude product, which was purified from re-crystallizationfrom ether to give desired compound (Yield: 55% yield). ¹HNMR (CDCl₃,300 MHz) δ 2.01 (m, 3H), 4.62 (m, 1H), 7.41 (s, 1H), 8.58 (br s, 1H),9.35 (s, 1H).

Step b: Synthesis ofN-(4,6-dichloropyridin-3-yl)-N²-(3-methylbutyl)alaninamide

To a stirred solution of 2-bromo-N-(4,6-dichloropyridin-3-yl)propanamide(500 mg, 1.68 mmol) in DMF (4 mL) was added potassium carbonate (465 mg,3.36 mmol) and isoamylamine (4, 0.512 mg, 5.88 mmol), the reactionmixture was then heated to 80° C. and stirred at the same temperaturefor 2 h. The reaction mixture was then cooled to rt, diluted with water(20 mL) and extracted with ethyl acetate (25 mL×3). The combined organicphases were washed with water, dried over Na₂SO₄ and evaporated to givea crude residue, which was purified by silica gel column chromatography(eluent: 25% ethyl acetate in hexane) to give desired product (Yield:69%). ¹HNMR (CDCl₃, 300 MHz) δ 0.91-0.98 (m, 6H), 1.39-1.43 (m, 3H),1.60-1.75 (m, 2H), 2.59-2.76 (m, 2H), 3.22-3.31 (m, 2H), 7.41 (s, 1H),9.51 (s, 1H), 10.20 (br s, 1H).

Step c: Synthesis of7-chloro-2-methyl-1-(3-methylbutyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one

To a stirred solution ofN-(4,6-dichloropyridin-3-yl)-N²-(3-methylbutyl)alaninamide (350 mg, 1.15mmol) in DMF (1.0 mL) was added tri-basic potassium phosphate (250 mg,1.20 mmol). The reaction mixture was heated to 125° C. and stirred atthe same temperature for 3 h. The reaction was then cooled to rt,diluted with water (5 mL) and the aqueous phase was extracted with ethylacetate (25 mL×3). The combined organic phases were washed with water,dried over Na₂SO₄ and evaporated to give desired product (Yield: 33%),which was used for next step without any further purifications. ¹HNMR(CDCl₃, 300 MHz) δ 0.90-1.01 (m, 6H), 1.33 (d, 3H), 1.52-1.75 (m, 2H),1.80 (s, 1H), 3.10-3.19 (m, 1H), 3.31-3.42 (m, 1H), 4.07 (q, 1H), 6.51(s, 1H), 7.65 (s, 1H), 9.41 (br s, 1H).

Step d: Synthesis of7-chloro-2-methyl-1-(3-methylbutyl)-4-phenyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one

To a stirred solution of7-chloro-2-methyl-1-(3-methylbutyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one(103 mg, 0.38 mmol) in dichloromethane (7 mL) was added triethylamine(0.53 mL, 3.8 mmol), cupric acetate (140 mg, 0.77 mmol) andphenylboronic acid (94 mg, 0.77 mmol) followed by 4 Å molecular sieves(2.0 g). The reaction mixture was stirred for 30 h at rt with an airballoon. It was then filtered over celite to remove inorganic material,the organic phase was washed with aqueous sodium carbonate, dried withNa₂SO₄, and the solvent was removed under reduced pressure to give acrude residue, which was purified by silica gel flash columnchromatography (eluent: 40% ethyl acetate in hexane) to give the desiredproduct (Yield: 49%). ¹HNMR (CDCl₃, 300 MHz) δ 1.07-1.18 (m, 6H), 1.47(d, J=6.6 Hz, 3H), 1.69-1.86 (m, 4H), 3.18-3.26 (m, 1H), 3.48-3.58 (m,1H), 4.32 (q, J=6.9 Hz, 1H), 6.62 (s, 1H), 6.87-7.05 (m, 1H), 7.27-7.35(m, 2H), 7.39 (s, 1H), 7.53-7.65 (m, 3H).

Step e: Synthesis of2-methyl-1-(3-methylbutyl)-4-phenyl-7-{[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]amino}-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one

To a stirred mixture of7-chloro-2-methyl-1-(3-methylbutyl)-4-phenyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one(25.00 mg, 0.073 mmol) and 5-amino-1-(tetrahydropyranyl)-1H-indazole (23mg, 0.11 mmol) in toluene (2.00 mL) was addedbis(dibenzylideneacetone)palladium (10.0 mg, 0.011 mmol),2,2′-Bis-diphenylphosphanyl-[1,1′]binaphthalenyl (13.5 mg, 0.022 mmol)and Cs₂CO₃ (71 mg, 0.22 mmol). The resulting mixture was heated at 95°C. for 5 h. LC-MS indicated completion of reaction. The bulk of solventwas removed under reduced pressure to give a crude residue, which waspurified by flash column chromatography on silica gel (eluent: 2%methanol in dichloromethane) to give the desired product: (Yield: 65%)MS(ES⁺): m/z 525.21 [MH⁺]. HPLC: t_(R)=3.26 (ZQ3, Polar_5 min).

Step f: Synthesis of7-(1H-indazol-5-ylamino)-2-methyl-1-(3-methylbutyl)-4-phenyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one

To a stirred solution of2-methyl-1-(3-methylbutyl)-4-phenyl-7-{[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]amino}-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one(15 mg) in dioxane (2 mL) was added 2N aq. HCl (2 mL) at rt. Theresulting mixture was stirred at rt for 2 h. LC-MS indicated completionof reaction. Dichloromethane (30 mL) was added to the reaction mixture,the organic phase was washed with aq. NaHCO₃, dried over anhydroussodium sulfate, and evaporated to give a residue, which was purified bypreparative Thin-Layer Chromatography (developing solvent: 2% methanolin dichloromethane) to give the desired product (yield: 60%) ¹H NMR (400MHz, CD₃OD) b 0.88 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H), 1.41 (d,J=6.82 Hz, 3H), 1.55-1.65 (m, 3H), 3.18-3.28 (m, 1H), 3.39-3.49 (m, 1H),4.26 (q, J=6.74 Hz, 1H), 6.10 (s, 1H), 6.79 (s, 1H), 7.27-7.34 (m, 3H),7.49-7.55 (m, 2H), 7.56-7.62 (m, 2H), 7.75 (d, J=1.52 Hz, 1H), 7.97 (s,1H). MS(ES⁺): m/z 441.19 [MH⁺]. HPLC: t_(R)=2.55 (ZQ3, Polar_5 min).

Ex. # Chemical Name Analytical data 311 3-[(7R)-8-(3,3- ¹H NMR (CDCl₃,300 MHz) δ 1.16 (s, 3H), 1.30 dimethylcyclobutyl)-2-[(7-fluoro- (s, 3H),1.38 (d, J = 6.6 Hz, 3H), 1.86-1.99 (m, 1H-indazol-5-yl)amino]-7-methyl-2H), 2.15-2.24 (m, 1H), 2.45-2.52 (m, 1H), 4.40-6-oxo-7,8-dihydropteridin-5(6H)- 4.50 (m, 2H), 7.03-7.18 (m, 2H),7.44-7.48 (m, yl]benzonitrile 1H), 7.53-7.56 (m, 1H), 7.62-7.68 (m, 2H),7.73- 7.76 (m, 2H), 8.03 (brs, 1H); [α]_(D) = +18 (c = 0.55 in CH₂Cl₂).MS(ES⁺): m/z 496.75 [MH⁺]. HPLC: t_(R) = 2.80 (ZQ3, Polar_5 min). 3123-[(7R)-8-(3,3- ¹H NMR (CDCl₃, 300 MHz) δ 1.13 (s, 3H), 1.23dimethylcyclobutyl)-7-methyl-6- (s, 3H), 1.44 (d, J = 6.9 Hz, 3H),1.82-1.99 (m, oxo-2-(1H-pyrazolo[3,4- 2H), 2.15-2.20 (m, 1H), 2.30-2.38(m, 1H), 4.44- b]pyridin-5-ylamino)-7,8- 4.48 (m, 2H), 7.14 (s, 1H),7.55 (d, J = 8.7 Hz, dihydropteridin-5(6H)- 1H), 7.62 (s, 1H), 7.69 (t,J = 7.5 Hz, 1H), 7.99 yl]benzonitrile (d, J = 7.5 Hz, 1H), 8.04 (s, 1H),8.66 (s, 2H), 8.90 (brs, 1H). MS(ES⁺): m/z 479.74 [MH⁺]. HPLC: t_(R) =2.58 (ZQ3, Polar_5 min). 313 3-[(7R)-8-(3,3- MS(ES⁺): m/z 504.77 [MH⁺].HPLC: t_(R) = 2.69 difluorocyclobutyl)-2-[(7-fluoro- (ZQ3, Polar_5 min).1H-indazol-5-yl)amino]-7-methyl- 6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile

Example 311 was synthesized from 3,3-dimethylcyclobutanaminehydrochloride based on following chemistry (steps a-e), according tosimilar procedures described in steps b-f for synthesis of example 178.

Examples 312 and 313 were prepared according to procedures similar forthe preparation of Example 311, using corresponding starting materialsand intermediates. COMPOSITIONS

The invention includes pharmaceutical compositions comprising a compoundor pharmaceutically acceptable salt thereof of the invention, which isformulated for a desired mode of administration with or without one ormore pharmaceutically acceptable and useful carriers.

The compounds can also be included in pharmaceutical compositions incombination with one or more other therapeutically active compounds.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or a pharmaceutically acceptable saltthereof) as an active ingredient, optional pharmaceutically acceptablecarrier(s) and optionally other therapeutic ingredients or adjuvants.The compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions may be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Compounds of the invention can be combined as the active ingredient inintimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending on the form of preparation desired foradministration, e.g., oral or parenteral (including intravenous). Thus,the pharmaceutical compositions of the present invention can bepresented as discrete units suitable for oral administration such ascapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient. Further, the compositions can be presented as apowder, as granules, as a solution, as a suspension in an aqueousliquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as awater-in-oil liquid emulsion. In addition to the common dosage forms setout above, the compound represented by Formula I, or a pharmaceuticallyacceptable salt thereof, may also be administered by controlled releasemeans and/or delivery devices. The compositions may be prepared by anyof the methods of pharmacy. In general, such methods include a step ofbringing into association the active ingredient with the carrier thatconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both. The product can then be conveniently shaped into the desiredpresentation.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.05 mg to about 5 g of the activeingredient and each cachet or capsule preferably containing from about0.05 mg to about 5 g of the active ingredient.

A formulation intended for the oral administration to humans may containfrom about 0.5 mg to about 5 g of active agent, compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95 percent of the total composition. Unit dosageforms will generally contain between from about 1 mg to about 2 g of theactive ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Compounds of the invention can be provided for formulation at highpurity, for example at least about 90%, 95%, or 98% pure by weight.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or a pharmaceutically acceptable saltthereof, via conventional processing methods. As an example, a cream orointment is prepared by admixing hydrophilic material and water,together with about 5 wt % to about 10 wt % of the compound, to producea cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

Biological Properties

In some embodiments, compounds of the invention are inhibitors ofkinases. Without limitation to the invention, compounds of the inventionhave been determined to have utility in their RSK inhibition activity.In some embodiments, the compounds are inhibitors of one or more ofRSK1-4. In some embodiments, the compounds are inhibitors of allisoforms RSK1-4. In some embodiments, the compounds are inhibitors of atleast RSK1-2. Of note, the example compounds assayed for RSK1 and RSK2were found to have activity against both kinases.

In some embodiments, a compound of the invention inhibits RSK1 and/orRSK2 in a biochemical assay with an IC₅₀ of about 100 nM or less. Theassay can be such as that described herein or another assay. In someembodiments, the IC₅₀s may be about 10 nM or less, about 100 nM or less,or about 1 μM or less.

In some embodiments, the compound is selective for RSK1 and/or RSK2 withrespect to certain other non-RSK kinases. In some embodiments, thecompound is selective for all of RSK1-4 over certain other kinases. Insome embodiments the selectivity is with respect to one or more of:polo-like kinase 1 (PLK1), aurora kinases, or KDR. In some embodiments,this selectivity is about 10-fold or more, about 25-fold or more, about50-fold or more, about 100-fold or more, or about 500-fold or more inassays such as biochemical or cellular assays.

In some embodiments, the compound is sufficiently orally bioavailablefor effective human administration. In some embodiments, the compound ischaracterized by a suitable therapeutic window upon humanadministration, oral or otherwise.

RSK1 & RSK2 Omnia Assay Protocol for Compound IC₅₀ Determination

The Omnia Assay (Invitrogen) has been optimized for His-tagged fulllength RSK1 (RPS6KA1, Millipore 14-509) and for His-tagged full-lengthRSK2 (RPS6KA3, Invitrogen PV3323). In this assay system, Omnia STPeptide 6 (Invitrogen KNZ1061) functions as a substrate for RSK1 orRSK2. Phosphorylation of this SOX-containing peptide results in anincrease in fluorescence at 485 nm upon excitation at 360 nm.

Assays are carried out in 384-well OptiPlates (Perkin Elmer 6007290) ina total volume of 20 μL containing RSK1 (120 μM) or RSK2 (135 μM), OmniaST Peptide 6 (5 μM), ATP (15 μM, K_(m)=16.3 μM), and test compound(variable) in RSK assay buffer (50 mM HEPES, pH 7.5, 10 mM MgCl₂, 0.01%Tween-20, 1% glycerol, 1 mM DTT, 1 mM EGTA, 0.01% BSA) with 1% DMSO.

IC₅₀s for test compounds are typically determined using an 11-pointthree-fold serial dilution with a final assay concentration rangingeither from 170 μM to 10 μM or from 17 μM to 1 μM. All compoundconcentrations are assayed in duplicate. Initial compound dilutions areprepared at 100× concentration in 100% DMSO from a 10 mM stock solution.Compounds are further diluted 1:25 in assay buffer resulting in a 4×concentrated solution.

To run the assay 5 μL of the above 4× concentrated compound solution (or4% DMSO for positive controls) is added to the assay plate followed by 5μL of a solution containing peptide (20 μM) and ATP (60 μM) in assaybuffer. The reaction is initiated by the addition of 10 μL of RSK1 (240μM) or RSK2 (270 μM) in assay buffer, or assay buffer alone for negativecontrols. The increase in fluorescence due to peptide phosphorylation ismonitored continuously as a function of time using a Spectramax M5 platereader (Molecular Devices) equipped with SoftMax Pro software.

The slopes from the linear portion of progress curves are used todetermine IC₅₀ values by non-linear curve-fitting to a four-parameterequation using GraphPad Prism (GraphPad Software, Inc.) or XLFit (IDBS).IC₅₀'s are determined in duplicate (n=2) and K_(i) values are calculatedfrom IC₅₀ values using the Cheng-Prusoff equation assuming a competitivemode of inhibition.

The RSK2 biochemical potency of compounds described herein are shown inTable 1. Results are shown in Table 1 according to the key: A, IC₅₀≦0.1μM; B, 0.1 μM<IC₅₀≦1 μM; C, IC₅₀>1 μM.

TABLE 1 Example # Mean RSK2 Biochem IC50 1 A 2 A 3 A 4 C 5 B 6 B 7 C 8 C9 C 10 C 11 C 12 C 13 B 14 A 15 C 16 A 17 A 18 A 19 A 20 A 21 A 22 A 23A 24 A 25 A 26 A 27 A 28 A 29 A 30 A 31 A 32 A 33 B 34 A 35 A 36 A 37 A38 A 39 A 40 A 41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 A 49 A 50 A 51 A 52A 53 A 54 A 55 A 56 A 57 A 58 A 59 B 60 A 61 A 62 B 63 A 64 A 65 A 66 A67 B 68 A 69 A 70 A 71 A 72 A 73 C 74 A 75 A 76 A 77 B 78 C 79 A 80 A 81A 82 A 83 A 84 B 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A 93 A 94 B 95 A96 A 97 A 98 A 99 A 100 A 101 C 102 B 103 B 104 A 105 A 106 A 107 B 108A 109 B 110 A 111 A 112 A 113 A 114 A 115 A 116 A 117 B 118 A 119 C 120A 121 A 122 A 123 B 124 A 125 A 126 A 127 A 128 A 129 A 130 A 131 A 132A 133 A 134 A 135 A 136 A 137 A 138 A 139 A 140 A 141 A 142 A 143 A 144A 145 A 146 A 147 A 148 A 149 A 150 A 151 A 152 A 153 A 154 A 155 A 156B 157 B 158 A 159 A 160 A 161 A 162 C 163 C 164 A 165 A 166 A 167 B 168B 169 A 170 C 171 A 172 A 173 A 174 A 175 A 176 A 177 A 178 A 179 B 180A 181 A 182 A 183 A 184 A 185 A 186 A 187 A 188 A 189 A 190 A 191 A 192A 193 A 194 A 195 A 196 A 197 A 198 A 199 A 200 A 201 A 202 A 203 A 204A 205 A 206 A 207 A 208 A 209 A 210 A 211 A 212 A 213 A 214 A 215 A 216A 217 A 218 A 219 A 220 A 221 A 222 A 223 A 224 A 225 A 226 A 227 A 228A 229 A 230 B 231 A 232 A 233 A 234 A 235 A 236 A 237 A 238 A 239 A 240A 241 A 242 A 243 A 244 A 245 A 246 A 247 A 248 A 249 A 250 B 251 A 252A 253 A 254 A 255 A 256 A 257 A 258 A 259 A 260 A 261 A 262 A 263 A 264A 265 C 266 A 267 A 268 B 269 A 270 A 271 A 272 A 273 A 274 B 275 C 276A 277 A 278 A 279 A 280 A 281 A 282 A 283 B 284 B 285 A 286 B 287 A 288A 289 A 290 A 291 A 292 A 293 A 294 A 295 A 296 A 297 A 298 A 299 A 300A 301 A 302 A 303 A 304 A 305 C 306 C 307 B 308 A 309 C 310 B

The RSK1 biochemical potency of examples 23, 29, 57, 66 are shown inTable 2. Results are shown in Table 2 according to the key: A, IC₅₀≦0.1μM; B, 0.1 μM<IC₅₀≦1 μM; C, IC₅₀>1 μM.

TABLE 2 Example # Mean RSK1 Biochem IC₅₀ 23 A 29 A 57 A 66 AUses

In view of their biological activity, compounds of the invention andcompositions thereof are useful whenever inhibition of RSK may bebeneficial. The compounds may be useful in the treatment and/orprevention of various diseases and conditions such as hyperproliferativedisorders such as cancer. Cancers can include solid tumors, leukemias,and lymphomas. In some embodiments, the condition is other than cancer.

In some embodiments, the invention includes a method of inhibiting atleast RSK1 and RSK2 in a cell, comprising contacting the cell with aneffective amount of the compound or salt. In some embodiments, theinvention includes inhibiting cell proliferation or cell growth bycontacting cells with an effective amount of the compound or salt.

In some embodiments, the invention includes a method of treating cancermediated at least in part by RSK1 and RSK2, comprising administering toa human in need thereof a therapeutically effective amount of thecompound.

In some embodiments, the invention includes the compound or salt thereofformulated for use in treating human disease such as but not limited tocancer that is mediated at least in part by RSK1 and RSK2.

In some embodiments, the cancer may be a solid tumor, sarcoma,fibrosarcoma, osteoma, melanoma, retinoblastoma, rhabdomyosarcoma,glioblastoma, neuroblastoma, teratocarcinoma, hematopoietic malignancy,and malignant ascites. More specifically, the cancers include, but notlimited to, lung cancer, bladder cancer, pancreatic cancer, kidneycancer, gastric cancer, breast cancer, colon cancer, prostate cancer(including bone metastases), hepatocellular carcinoma (HCC), ovariancancer, esophageal squamous cell carcinoma, melanoma, an anaplasticlarge cell lymphoma, an inflammatory myofibroblastic tumor, and aglioblastoma.

In some aspects, the above methods are used to treat one or more ofbladder, colorectal, nonsmall cell lung (NSCLC), breast, or pancreaticcancer. In some aspects, the above methods are used to treat one or moreof ovarian, gastric, head and neck, prostate, hepatocellular, renal,glioma, glioma, or sarcoma cancer.

In some embodiments, the invention includes a method of treating acancer selected from breast, prostate, multiple myeloma, head and necksquamous cell carcinoma (HNSCC), or acute myeloid leukemia (AML),comprising administering to a human in need thereof a therapeuticallyeffective amount of the compound or salt thereof.

In some embodiments, the invention includes a method of treating acardiovascular, inflammatory, allergic, pulmonary, fibrotic, or renaldisease that is mediated at least in part by RSK1 and/or RSK2,comprising administering to a human in need thereof a therapeuticallyeffective amount of the compound or salt.

In some embodiments, the invention includes a method as described above,further comprising administering a therapeutically effective amount ofat least one additional anti-cancer agent that is known at any time tobe effective in such combination.

In some embodiments, the invention includes use of a therapeuticallyeffective amount of a compound or salt the invention in the manufactureof a medicament for use in any of the treatment methods describedherein.

Generally, dosage levels on the order of from about 0.01 mg/kg to about150 mg/kg of body weight per day are useful in the treatment of theabove-indicated conditions, or alternatively about 0.5 mg to about 7 gper patient per day. For example, inflammation, cancer, psoriasis,allergy/asthma, disease and conditions of the immune system, disease andconditions of the central nervous system, may be effectively treated bythe administration of from about 0.01 mg to 1 g of the compound perkilogram of body weight per day, about 0.01 mg to 100 mg/kg, about 0.01mg to 10 mg/kg, or alternatively about 0.5 mg to about 3.5 g per patientper day.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

GENERAL DEFINITIONS AND ABBREVIATIONS

Except where otherwise indicated, the following general conventions anddefinitions apply. Unless otherwise indicated herein, language and termsare to be given their broadest reasonable interpretation as understoodby the skilled artisan. Any examples given are nonlimiting.

Any section headings or subheadings herein are for the reader'sconvenience and/or formal compliance and are non-limiting.

A recitation of a compound herein is open to and embraces any materialor composition containing the recited compound (e.g., a compositioncontaining a racemic mixture, tautomers, epimers, stereoisomers, impuremixtures, etc.). In that a salt, solvate, or hydrate, polymorph, orother complex of a compound includes the compound itself, a recitationof a compound embraces materials containing such forms. Isotopicallylabeled compounds are also encompassed except where specificallyexcluded. For example, hydrogen is not limited to hydrogen containingzero neutrons.

The term “active agent” of the invention means a compound of theinvention in any salt, polymorph, crystal, solvate, or hydrated form.

The term “pharmaceutically acceptable salt(s)” is known in the art andincludes salts of acidic or basic groups which can be present in thecompounds and prepared or resulting from pharmaceutically acceptablebases or acids.

The term “substituted” and substitutions contained in formulas hereinrefer to the replacement of one or more hydrogen radicals in a givenstructure with a specified radical, or, if not specified, to thereplacement with any chemically feasible radical. When more than oneposition in a given structure can be substituted with more than onesubstituent selected from specified groups, the substituents can beeither the same or different at every position (independently selected)unless otherwise indicated. In some cases, two positions in a givenstructure can be substituted with one shared substituent. It isunderstood that chemically impossible or highly unstable configurationsare not desired or intended, as the skilled artisan would appreciate.

In descriptions and claims where subject matter (e.g., substitution at agiven molecular position) is recited as being selected from a group ofpossibilities, the recitation is specifically intended to include anysubset of the recited group. In the case of multiple variable positionsor substituents, any combination of group or variable subsets is alsocontemplated. Unless indicated otherwise, a substituent, diradical orother group referred to herein can be bonded through any suitableposition to a referenced subject molecule. For example, the term“indolyl” includes 1-indolyl, 2-indolyl, 3-indolyl, etc.

The convention for describing the carbon content of certain moieties is“(C_(a-b))” or “C_(a)-C_(b)” meaning that the moiety can contain anynumber of from “a” to “b” carbon atoms. C₀alkyl means a single covalentchemical bond when it is a connecting moiety, and a hydrogen when it isa terminal moiety. Similarly, “x-y” can indicate a moiety containingfrom x to y atoms, e.g., ₅₋₆heterocycloalkyl means a heterocycloalkylhaving either five or six ring members. “C_(x-y)” may be used to definenumber of carbons in a group. For example, “C₀₋₁₂alkyl” means alkylhaving 0-12 carbons, wherein C₀alkyl means a single covalent chemicalbond when a linking group and means hydrogen when a terminal group.

The term “absent,” as used herein to describe a structural variable(e.g., “—R— is absent”) means that diradical R has no atoms, and merelyrepresents a bond between other adjoining atoms, unless otherwiseindicated.

Unless otherwise indicated (such as by a connecting “-”), theconnections of compound name moieties are at the rightmost recitedmoiety. That is, the substituent name starts with a terminal moiety,continues with any bridging moieties, and ends with the connectingmoiety. For example, “heteroarylthioC₁₋₄alkyl is a heteroaryl groupconnected through a thio sulfur to a C₁₋₄ alkyl, which alkyl connects tothe chemical species bearing the substituent.

The term “aliphatic” means any hydrocarbon moiety, and can containlinear, branched, and cyclic parts, and can be saturated or unsaturated.

The term “alkyl” means any saturated hydrocarbon group that isstraight-chain or branched. Examples of alkyl groups include methyl,ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and thelike.

The term “alkenyl” means any ethylenically unsaturated straight-chain orbranched hydrocarbon group. Representative examples include, but are notlimited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, andthe like.

The term “alkynyl” means any acetylenically unsaturated straight-chainor branched hydrocarbon group. Representative examples include, but arenot limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl,and the like.

The term “alkoxy” means —O-alkyl, —O-alkenyl, or —O-alkynyl.“Haloalkoxy” means an —O-(haloalkyl) group. Representative examplesinclude, but are not limited to, trifluoromethoxy, tribromomethoxy, andthe like.

“Haloalkyl” means an alkyl that is substituted with one or more same ordifferent halo atoms.

“Hydroxyalkyl” means an alkyl that is substituted with one, two, orthree hydroxy groups; e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1,2-,1,3-, or 2,3-dihydroxypropyl, and the like.

The term “alkanoyl” means —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl.

“Alkylthio” means an —S-(alkyl) or an —S-(unsubstituted cycloalkyl)group. Representative examples include, but are not limited to,methylthio, ethylthio, propylthio, butylthio, cyclopropylthio,cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

The term “cyclic” means any ring system with or without heteroatoms (N,O, or S(O)₀₋₂), and which can be saturated or unsaturated. Ring systemscan be bridged and can include fused rings. The size of ring systems maybe described using terminology such as “_(x-y)cyclic,” which means acyclic ring system that can have from x to y ring atoms. For example,the term “₉₋₁₀carbocyclic” means a 5,6 or 6,6 fused bicyclic carbocyclicring system which can be satd., unsatd. or aromatic. It also means aphenyl fused to one 5 or 6 membered satd. or unsatd. carbocyclic group.Nonlimiting examples of such groups include naphthyl, 1,2,3,4tetrahydronaphthyl, indenyl, indanyl, and the like.

The term “carbocyclic” means a cyclic ring moiety containing only carbonatoms in the ring(s) without regard to aromaticity, includingmonocyclic, fused, and bridged systems. For example, a 3-10 memberedcarbocyclic means any chemically feasible ring systems having from 3 to10 ring atoms.

The term “cycloalkyl” means a non-aromatic 3-12 carbon mono-cyclic,bicyclic, or polycyclic aliphatic ring moiety. Cycloalkyl can bebicycloalkyl, polycycloalkyl, bridged, or spiroalkyl. One or more of therings may contain one or more double bonds but none of the rings has acompletely conjugated pi-electron system. Examples, without limitation,of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane,cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane,cycloheptatriene, and the like.

The term “unsaturated carbocyclic” means any cycloalkyl containing atleast one double or triple bond. The term “cycloalkenyl” means acycloalkyl having at least one double bond in the ring moiety.

The terms “bicycloalkyl” and “polycycloalkyl” mean a structureconsisting of two or more cycloalkyl moieties that have two or moreatoms in common. If the cycloalkyl moieties have exactly two atoms incommon they are said to be “fused”. Examples include, but are notlimited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. If thecycloalkyl moieties have more than two atoms in common they are said tobe “bridged”. Examples include, but are not limited to,bicyclo[2.2.1]heptyl (“norbornyl”), bicyclo[2.2.2]octyl, and the like.

The term “spiroalkyl” means a structure consisting of two cycloalkylmoieties that have exactly one atom in common. Examples include, but arenot limited to, spiro[4.5]decyl, spiro[2.3]hexyl, and the like.

The term “aromatic” means planar ring moieties containing 4n+2 pielectrons, wherein n is an integer.

The term “aryl” means an aromatic moieties containing only carbon atomsin its ring system. Non-limiting examples include phenyl, naphthyl, andanthracenyl. The terms “aryl-alkyl” or “arylalkyl” or “aralkyl” refer toany alkyl that forms a bridging portion with a terminal aryl.

“Aralkyl” means alkyl that is substituted with an aryl group as definedabove; e.g., —CH₂ phenyl, —(CH₂)₂phenyl, —(CH₂)₃phenyl,CH₃CH(CH₃)CH₂phenyl, and the like and derivatives thereof.

The term “heterocyclic” means a cyclic ring moiety containing at leastone heteroatom (N, O, or S(O)₀₋₂), including heteroaryl,heterocycloalkyl, including unsaturated heterocyclic rings.

The term “heterocycloalkyl” means a non-aromatic monocyclic, bicyclic,or polycyclic heterocyclic ring moiety of 3 to 12 ring atoms containingat least one ring having one or more heteroatoms. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples of heterocycloalkylrings include azetidine, oxetane, tetrahydrofuran, tetrahydropyran,oxepane, oxocane, thietane, thiazolidine, oxazolidine, oxazetidine,pyrazolidine, isoxazolidine, isothiazolidine, tetrahydrothiophene,tetrahydrothiopyran, thiepane, thiocane, azetidine, pyrrolidine,piperidine, N-methylpiperidine, azepane, 1,4-diazapane, azocane,[1,3]dioxane, oxazolidine, piperazine, homopiperazine, morpholine,thiomorpholine, 1,2,3,6-tetrahydropyridine and the like. Other examplesof heterocycloalkyl rings include the oxidized forms of thesulfur-containing rings. Thus, tetrahydrothiophene-1-oxide,tetrahydrothiophene-1,1-dioxide, thiomorpholine-1-oxide,thiomorpholine-1,1-dioxide, tetrahydrothiopyran-1-oxide,tetrahydrothiopyran-1,1-dioxide, thiazolidine-1-oxide, andthiazolidine-1,1-dioxide are also considered to be heterocycloalkylrings. The term “heterocycloalkyl” also includes fused ring systems andcan include a carbocyclic ring that is partially or fully unsaturated,such as a benzene ring, to form benzofused heterocycloalkyl rings. Forexample, 3,4-dihydro-1,4-benzodioxine, tetrahydroquinoline,tetrahydroisoquinoline and the like. The term “heterocycloalkyl” alsoincludes heterobicycloalkyl, heteropolycycloalkyl, or heterospiroalkyl,which are bicycloalkyl, polycycloalkyl, or spiroalkyl, in which one ormore carbon atom(s) are replaced by one or more heteroatoms selectedfrom O, N, and S. For example, 2-oxa-spiro[3.3]heptane,2,7-diaza-spiro[4.5]decane, 6-oxa-2-thia-spiro[3.4]octane,octahydropyrrolo[1,2-a]pyrazine, 7-aza-bicyclo[2.2.1]heptane,2-oxa-bicyclo[2.2.2]octane, and the like, are such heterocycloalkyls.

Examples of saturated heterocyclic groups include, but are not limitedto oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl,1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl,oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl,1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thieazepanyl, 1,4-diazepanyl

Non-aryl heterocyclic groups include satd. and unsatd. systems and caninclude groups having only 4 atoms in their ring system. Theheterocyclic groups include benzo-fused ring systems and ring systemssubstituted with one or more oxo moieties. Recitation of ring sulfur isunderstood to include the sulfide, sulfoxide or sulfone where feasible.The heterocyclic groups also include partially unsatd. or fully satd.4-10 membered ring systems, e.g., single rings of 4 to 8 atoms in sizeand bicyclic ring systems, including aromatic 6-membered aryl orheteroaryl rings fused to a non-aromatic ring. Also included are 4-6membered ring systems (“4-6 membered heterocyclic”), which include 5-6membered heteroaryls, and include groups such as azetidinyl andpiperidinyl. Heterocyclics can be heteroatom-attached where such ispossible. For instance, a group derived from pyrrole can be pyrrol-1-yl(N-attached) or pyrrol-3-yl (C-attached). Other heterocyclics includeimidazo(4,5-b)pyridin-3-yl and benzoimidazol-1-yl.

Examples of heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,3H-indolyl, quinolizinyl, and the like.

The term “unsaturated heterocyclic” means a heterocycloalkyl containingat least one unsaturated bond. The term “heterobicycloalkyl” means abicycloalkyl structure in which at least one carbon atom is replacedwith a heteroatom. The term “heterospiroalkyl” means a spiroalkylstructure in which at least one carbon atom is replaced with aheteroatom.

Examples of partially unsaturated heteroalicyclic groups include, butare not limited to: 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl,2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, and1,2,5,6-tetrahydropyridinyl.

The terms “heteroaryl” or “hetaryl” mean a monocyclic, bicyclic, orpolycyclic aromatic heterocyclic ring moiety containing 5-12 atoms.Examples of such heteroaryl rings include, but are not limited to,furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.The terms “heteroaryl” also include heteroaryl rings with fusedcarbocyclic ring systems that are partially or fully unsaturated, suchas a benzene ring, to form a benzofused heteroaryl. For example,benzimidazole, benzoxazole, benzothiazole, benzofuran, quinoline,isoquinoline, quinoxaline, and the like. Furthermore, the terms“heteroaryl” include fused 5-6, 5-5, 6-6 ring systems, optionallypossessing one nitrogen atom at a ring junction. Examples of suchhetaryl rings include, but are not limited to, pyrrolopyrimidinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,imidazo[4,5-b]pyridine, pyrrolo[2,1-f][1,2,4]triazinyl, and the like.Heteroaryl also includes N-oxide moieties where applicable. Heteroarylgroups may be attached to other groups through their carbon atoms or theheteroatom(s), if applicable. For example, pyrrole may be connected atthe nitrogen atom or at any of the carbon atoms.

Heteroaryls include, e.g., 5 and 6 membered monocyclics such aspyrazinyl and pyridinyl, and 9 and 10 membered fused bicyclic ringmoieties, such as quinolinyl. Other examples of heteroaryl includequinolin-4-yl, 7-methoxy-quinolin-4-yl, pyridin-4-yl, pyridin-3-yl, andpyridin-2-yl. Other examples of heteroaryl include pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl,pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl,thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, furopyridinyl, and the like. Examples of 5-6 memberedheteroaryls include, thiophenyl, isoxazolyl, 1,2,3-triazolyl,1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-triazolyl,1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-oxadiazolyl,1,2,5-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4oxadiazolyl, 1,2,5-triazinyl, 1,3,5-triazinyl, and the like.

“Heteroaralkyl” group means alkyl that is substituted with a heteroarylgroup; e.g., —CH₂ pyridinyl, —(CH₂)₂pyrimidinyl, —(CH₂)₃imidazolyl, andthe like, and derivatives thereof.

A pharmaceutically acceptable heteroaryl is one that is sufficientlystable to be attached to a compound of the invention, formulated into apharmaceutical composition and subsequently administered to a patient inneed thereof.

Examples of monocyclic heteroaryl groups include, but are not limitedto: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl,1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl,1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl,1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl.

Examples of fused ring heteroaryl groups include, but are not limitedto: benzoduranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl,benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl,imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl,indazolyl, purinyl, indolinyl, imidazo[1,2-a]pyridinyl,imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl,isoquinolinyl, cinnolinyl, azaquinazoline, quinoxalinyl, phthalazinyl,1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl,1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl,pyrimido[5,4-d]pyrimidinyl, pyrimido[2,3-b]pyrazinyl,pyrimido[4,5-d]pyrimidinyl.

“Arylthio” means an —S-aryl or an —S-heteroaryl group, as definedherein. Representative examples include, but are not limited to,phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio,and the like and derivatives thereof.

The term “9-10 membered heterocyclic” means a fused 5,6 or 6,6 bicyclicheterocyclic ring moiety, which can be satd., unsatd. or aromatic. Theterm “9-10 membered fused bicyclic heterocyclic” also means a phenylfused to one 5 or 6 membered heterocyclic group. Examples includebenzofuranyl, benzothiophenyl, indolyl, benzoxazolyl,3H-imidazo[4,5-c]pyridin-yl, dihydrophthazinyl,1H-imidazo[4,5-c]pyridin-1-yl, imidazo[4,5-b]pyridyl, 1,3benzo[1,3]dioxolyl, 2H-chromanyl, isochromanyl, 5-oxo-2,3dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidyl, 1,3-benzothiazolyl, 1,4,5,6tetrahydropyridazyl, 1,2,3,4,7,8 hexahydropteridinyl,2-thioxo-2,3,6,9-tetrahydro-1H-purin-8-yl, 3,7-dihydro-1H-purin-8-yl,3,4-dihydropyrimidin-1-yl, 2,3-dihydro-1,4-benzodioxinyl,benzo[1,3]dioxolyl, 2H-chromenyl, chromanyl, 3,4-dihydrophthalazinyl,2,3-ihydro-1H-indolyl, 1,3-dihydro-2H-isoindol-2-yl,2,4,7-trioxo-1,2,3,4,7,8-hexahydropteridin-yl, thieno[3,2-d]pyrimidinyl,4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-yl,1,3-dimethyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purinyl,1,2-dihydroisoquinolinyl, 2-oxo-1,3-benzoxazolyl,2,3-dihydro-5H-1,3-thiazolo-[3,2-a]pyrimidinyl,5,6,7,8-tetrahydro-quinazolinyl, 4-oxochromanyl, 1,3-benzothiazolyl,benzimidazolyl, benzotriazolyl, purinyl, furylpyridyl,thiophenylpyrimidyl, thiophenylpyridyl, pyrrolylpiridyl,oxazolylpyridyl, thiazolylpiridyl, 3,4-dihydropyrimidin-1-ylimidazolylpyridyl, quinoliyl, isoquinolinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pyrazolyl[3,4]pyridine, 1,2-dihydroisoquinolinyl,cinnolinyl, 2,3-dihydro-benzo[1,4]dioxin4-yl,4,5,6,7-tetrahydro-benzo[b]-thiophenyl-2-yl, 1,8-naphthyridinyl,1,5-napthyridinyl, 1,6-naphthyridinyl, 1,7-napthyridinyl,3,4-dihydro-2H-1,4-benzothiazine, 4,8-dihydroxy-quinolinyl,1-oxo-1,2-dihydro-isoquinolinyl, 4-phenyl-[1,2,3]thiadiazolyl, and thelike.

“Aryloxy” means an —O-aryl or an —O-heteroaryl group, as defined herein.Representative examples include, but are not limited to, phenoxy,pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, andthe like, and derivatives thereof.

One in the art understands that an “oxo” requires a second bond from theatom to which the oxo is attached. Accordingly, it is understood thatoxo cannot be substituted onto an aryl or heteroaryl ring.

The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo.

“Acyl” means a —C(O)R group, where R can be selected from thenonlimiting group of hydrogen or optionally substituted alkyl,trihalomethyl, unsubstituted cycloalkyl, aryl. “Thioacyl” or“thiocarbonyl” means a —C(S)R” group, with R as defined above.

The term “protecting group” means a suitable chemical group that can beattached to a functional group and removed at a later stage to revealthe intact functional group. Examples of suitable protecting groups forvarious functional groups are described in T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 2d Ed., John Wiley andSons (1991 and later editions); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995). The term “hydroxy protecting group”, as usedherein, unless otherwise indicated, includes Ac, CBZ, and varioushydroxy protecting groups familiar to those skilled in the art includingthe groups referred to in Greene.

As used herein, the term “pharmaceutically acceptable salt” means thosesalts which retain the biological effectiveness and properties of theparent compound and do not present insurmountable safety or toxicityissues.

The term “pharmaceutical composition” means an active compound in anyform suitable for effective administration to a subject, e.g., a mixtureof the compound and at least one pharmaceutically acceptable carrier.

As used herein, a “physiologically/pharmaceutically acceptable carrier”means a carrier or diluent that does not cause significant irritation toan organism and does not abrogate the biological activity and propertiesof the administered compound.

A “pharmaceutically acceptable excipient” means an inert substance addedto a pharmaceutical composition to further facilitate administration ofa compound. Examples, without limitation, of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

The term “cancer” in an refers to the presence of cells possessingcharacteristics typical of cancer-causing cells, such as uncontrolledproliferation, immortality, metastatic potential, rapid growth andproliferation rate, and certain characteristic morphological features.Often, cancer cells will be in the form of a tumor, but such cells mayexist alone within an animal, or may circulate in the blood stream asindependent cells, such as leukemic cells.

The terms “treat,” “treatment,” and “treating” means reversing,alleviating, inhibiting the progress of, or partially or completelypreventing the disorder or condition to which such term applies, or oneor more symptoms of such disorder or condition. “Preventing” meanstreating before an infection occurs.

“Therapeutically effective amount” means that amount of the compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disorder being treated, or result in inhibition of theprogress or at least partial reversal of the condition.

The following abbreviations are used:

-   -   min. minute(s)    -   h hour(s)    -   d day(s)    -   RT or rt room temperature    -   t_(R) retention time    -   L liter    -   mL milliliter    -   mmol millimole    -   μmol micromole    -   equiv. or eq. equivalents    -   NMR nuclear magnetic resonance    -   MDP(S) mass-directed HPLC purification (system)    -   LC/MS liquid chromatography mass spectrometry    -   HPLC high performance liquid chromatography    -   TLC thin layer chromatography    -   CDCl₃ deuterated chloroform    -   CD₃OD or MeOD deuterated methanol    -   DMSO-d₆ deuterated dimethylsulfoxide    -   LDA lithium diisopropylamide    -   DCM dichloromethane    -   THF tetrahydrofuran    -   EtOAc ethyl acetate    -   MeCN acetonitrile    -   DMSO dimethylsulfoxide    -   Boc tert-butyloxycarbonyl    -   DME 1,2-dimethoxyethane    -   DMF N,N-dimethylformamide    -   DIPEA diisopropylethylamine    -   PS-DIEA polymer-supported diisopropylethylamine    -   PS-PPh₃-Pd polymer-supported Pd(PPh₃)₄    -   EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide    -   HOBt 1-hydroxybenzotriazole    -   DMAP 4-dimethylaminopyridine    -   TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        tetrafluoroborate    -   TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl    -   TFA trifluoroacetic acid    -   OTf Trifluoromethanesulfonate

The invention claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: A₁ is N; A₂ isC(O) or C(R⁵)(R⁶); R¹ is phenyl optionally fused to 5-10 memberedcyclic, or R¹ is 5-6 membered heteroaryl optionally fused to 5-10membered cyclic, either of which is optionally substituted by one ormore R⁷; each R⁷ is independently halo, nitro, —CN, —OR¹⁰, —NR¹⁰R¹¹,—C(O)R¹⁰, —C(O)OR¹⁰, —C(O)NR¹⁰R¹¹, —SR¹⁰, —R¹⁰, —NR¹²C(O)NR¹⁰R¹¹,—OC(O)R¹⁰, —NR¹²C(O)R¹, —NR¹²C(O)OR¹⁰, —OC(O)NR¹⁰R¹¹, —C(O)—C(O)OR¹⁰,—S(O₁₋₂)R¹⁰, —S(O₁₋₂)NR¹⁰R¹¹, —NR¹²S(O₁₋₂)R¹⁰, —NR¹²S(O₁₋₂)NR¹⁰R¹¹,—NR¹²S(O₁₋₂)OR¹⁰, or —OS(O₁₋₂)NR¹⁰R¹¹; or —PR¹⁰R¹¹, —P(OR¹⁰)(OR¹¹),—PR¹⁰(OR¹¹), —P(O)R¹⁰R¹¹, —P(O)(OR¹⁰)(OR¹¹), —P(O)R¹⁰(OR¹¹), —BR¹⁰R¹¹,—B(OR¹⁰)(OR¹¹), —NHS(O)(R¹⁰)═NR¹¹, or —R¹⁰—S(O)(R¹¹)═NR¹²; wherein inthe case of a non-aromatic moiety, an R⁷ can also be oxo; each R¹⁰, R¹¹,and R¹² is independently H or C₁₋₆aliphatic, each independentlyoptionally substituted by one or more halo, oxo, nitro, —CN, —OR¹³,—NR¹³R¹⁴, —C(O)R¹³, —C(O)OR¹³, —C(O)NR¹³R¹⁴, —SR¹³, —R¹⁴,—NR¹⁵C(O)NR¹³R¹⁴, —OC(O)R¹³, —NR¹⁴C(O)R¹³, —NR¹⁴C(O)OR¹³, —OC(O)NR¹³R¹⁴,—C(O)—C(O)OR¹³, —S(O₁₋₂)R¹³, —S(O₁₋₂)NR¹³R¹⁴, or —NR¹³S(O₁₋₂)R¹⁴;—NR¹⁵S(O₁₋₂)NR¹³R¹⁴, —NR¹⁵S(O₁₋₂)OR¹³, or —OS(O₁₋₂)NR¹³R¹⁴, or by—PR¹³R¹⁴, —P(OR¹³)(OR¹⁴), —PR¹³(OR¹⁴), —P(O)R¹³R¹⁴, —P(O)(OR¹³)(OR¹⁴),—P(O)R¹³(OR¹⁴), —BR¹³R¹⁴, —B(OR¹³)(OR¹⁴), —NHS(O)(R¹³)═NR¹⁴, or—R¹³—S(O)(R¹⁴)═NR¹⁵; wherein any R¹⁰/R¹¹ pair attached to the same atom,together with said atom to which they are attached, can form a 3-6membered cyclic that can include one or more heteroatoms selected fromO, NR¹⁸, or S(O₀₋₂); each R¹³, R¹⁴, and R¹⁵ is independently H orC₁₋₃aliphatic, each independently optionally substituted by one or morehalo, —CN, —OR¹⁶, —NR¹⁶R¹⁷, —C(O)R¹⁶, —C(O)OR¹⁶, —C(O)NR¹⁶, or—OC(O)R¹⁶; wherein any R¹³/R¹⁴ pair attached to the same atom, togetherwith said atom to which they are attached, can form a 3-6 memberedcyclic that can include one or more heteroatoms selected from O, NR¹⁹,or S(O₀₋₂); each R¹⁶, R¹⁷, R¹⁸, and R¹⁹ is independently H orC₁₋₃aliphatic; R² is phenyl or 5-6 membered heteroaryl each optionallysubstituted with one or more R²⁰; or R² is H or C₁₋₈aliphatic that isoptionally interrupted by one or more heteroatoms and optionallysubstituted by one or more R²¹; R³ is C₄₋₈carbocyclic optionally fusedto 5-10 membered cyclic or 5-6 membered heteroaryl optionally fused to5-10 membered cyclic, either of which is optionally substituted by oneor more R⁸; R⁴ is H, halo, C₁₋₃aliphatic, or —OC₁₋₃aliphatic; each R⁵and R⁶ is independently H, C₁₋₆aliphatic, or 3-10 membered cyclic, anyof which is optionally substituted by one or more halo, —OH,—OC₁₋₃aliphatic, —NR⁴⁰R⁴¹, 5-6 membered heteroaryl, or —C(O)NR⁴⁰R⁴¹;each R⁸ is independently halo, nitro, —CN, —OR³⁰, —NR³⁰R³¹, —C(O)R³⁰,—C(O)OR³⁰, —C(O)NR³⁰R³¹, —SR³⁰, —R³⁰, —NR³²C(O)NR³⁰R³¹, —OC(O)R³⁰,—NR³²C(O)R³⁰, —NR³²C(O)OR³⁰, —OC(O)NR³⁰R³¹, —C(O)—C(O)OR³⁰, —S(O₁₋₂)R³⁰,—S(O₁₋₂)NR³⁰R³¹, —NR³²S(O₁₋₂)R³⁰, —NR³²S(O₁₋₂)NR³⁰R³¹, —NR³¹S(O₁₋₂)OR³²,or —OS(O₁₋₂)NR³⁰R³¹; or —PR³⁰R³¹, —P(OR³⁰)(OR³¹), —PR³⁰(OR³¹),—P(O)R³R³¹, —P(O)(OR³⁰)(OR³¹), —P(O)R³⁰(OR³¹), —BR³⁰R³¹, —B(OR³⁰)(OR³¹),—NHS(O)(R³⁰)═NR³¹, or —R³⁰—S(O)(R³¹)═NR³²; wherein in the case of anon-aromatic moiety, an R⁸ can also be oxo; each R²⁰ and R²¹ isindependently oxo, —R²², halo, —CN, —OR²², —SR²², —NR²²R²³, —C(O)R²²,—C(O)OR²², —C(O)NR²², —OC(O)R²², NR²²C(O)R²³, —S(O₁₋₂)R²²,—S(O₁₋₂)NR²²R²³, or —NR²²S(O₁₋₂)R²³; each R²² and R²³ is independently Hor C₁₋₃aliphatic, each independently optionally substituted by one ormore oxo, —R⁵⁰, halo, —CN, —OR⁵⁰, —SR⁵⁰, —NR⁵⁰R⁵¹, —C(O)R⁵⁰, —C(O)OR⁵⁰,—C(O)NR⁵⁰, —OC(O)R⁵⁰, NR⁵⁰C(O)R⁵¹, —S(O₁₋₂)R⁵⁰, —S(O₁₋₂)NR⁵⁰R⁵¹, or—NR⁵⁰S(O₁₋₂)R⁵¹; wherein any R²²/R²³ pair attached to the same atom,together with said atom to which they are attached, can form a 3-6membered cyclic that can include one or more heteroatoms selected fromO, NR⁵², or S(O₀₋₂); each R³⁰, R³¹, and R³² is independently H orC₁₋₆aliphatic, each independently optionally substituted by one or morehalo, oxo, nitro, —CN, —OR³³, —NR³³R³⁴, —C(O)R³³, —C(O)OR³³,—C(O)NR³³R³⁴, —SR³³, —R³⁴, —OC(O)R³³, —NR³⁴C(O)R³³, —NR³⁴C(O)OR³³,—N═CR³³R³⁴, —OC(O)NR³³R³⁴, —C(O)—C(O)OR³³, —S(O₁₋₂)R³³, —S(O₁₋₂)NR³³R³⁴,or —NR³³S(O₁₋₂)R³⁴; or by —PR³³R³⁴, —P(OR³³)(OR³⁴), —PR³³(OR³⁴),—P(O)R³³R³⁴, —P(O)(OR³³)(OR³⁴), —P(O)R³³(OR³⁴), BR³³R³⁴, —B(OR³³)(OR³⁴),—NHS(O)(R³³)═NR³⁴, or —R³³—S(O)(R³⁴)═NR³⁵; wherein any R³⁰/R³¹ pairattached to the same atom, together with said atom to which they areattached, can form a 3-6 membered cyclic that can include one or moreheteroatoms selected from O, NR³⁸, or S(O₀₋₂); each R³⁰, R³⁴, and R³⁵ isindependently H or C₁₋₃aliphatic, each independently optionallysubstituted by one or more halo, —CN, —OR³⁶, —NR³⁶R³⁷, —C(O)R³⁶,—C(O)OR³⁶, —C(O)NR³⁶, or —OC(O)R³⁶; wherein any R³³/R³⁴ pair attached tothe same atom, together with said atom to which they are attached, canform a 3-6 membered cyclic that can include one or more heteroatomsselected from O, NR³⁹, or S(O₀₋₂); each R³⁶, R³⁷, R³⁸, and R³⁹ isindependently H or C₁₋₃aliphatic; each R⁴⁰ and R⁴¹ is independently H orC₁₋₃aliphatic, and R⁴⁰ and R⁴¹, together with the atom to which they areattached, can form a 3-6 membered cyclic optionally including one ormore heteroatoms; and each R⁵⁰, R⁵¹ and R⁵² is independently H orC₁₋₃aliphatic.
 2. The compound or salt of claim 1, wherein: each R⁵ andR⁶ is independently H or C₁₋₆aliphatic optionally substituted by one ormore halo, —OH, —OC₁₋₃aliphatic, —NR⁴⁰R⁴¹, 5-6 membered heteroaryl, or—C(O)NR⁴⁰R⁴¹; and each R⁴⁰ and R⁴¹ is independently H or C₁₋₃aliphatic,and R⁴⁰ and R⁴¹, together with the atom to which they are attached, canform a 3-6 membered cyclic optionally including one or more heteroatoms.3. The compound or salt of claim 2, wherein: R² is phenyl or 5-6membered heteroaryl, each optionally substituted by one or more R²⁰; orR² is C₁₋₈aliphatic optionally interrupted by one or more heteroatomsand optionally substituted by one or more R²¹; each R²⁰ and R²¹ isindependently oxo, —R²², halo, —CN, —OR²², —SR²², —NR²²R²³, —C(O)R²²,—C(O)OR²², —C(O)NR²², —OC(O)R²², NR²²C(O)R²³, —S(O₁₋₂)R²²,—S(O₁₋₂)NR²²R²³, or —NR²²S(O₁₋₂)R²³; each R²² and R²³ is independently Hor C₁₋₃aliphatic, each independently optionally substituted by one ormore oxo, —R⁵⁰, halo, —CN, —OR⁵⁰, —SR⁵⁰, —NR⁵⁰R⁵¹, —C(O)R⁵⁰, —C(O)OR⁵⁰,—C(O)NR⁵⁰, —OC(O)R⁵⁰, NR⁵⁰C(O)R⁵¹, —S(O₁₋₂)R⁵⁰, —S(O₁₋₂)NR⁵⁰R⁵¹, or—NR⁵⁰S(O₁₋₂)R⁵¹; wherein any R²²/R²³ pair attached to the same atom,together with said atom to which they are attached, can form a 3-6membered cyclic that can include one or more heteroatoms selected fromO, NR⁵², or S(O₀₋₂); and each R⁵⁰, R⁵¹ and R⁵² is independently H orC₁₋₃aliphatic.
 4. The compound or salt of claim 3, wherein: R³ is phenyloptionally fused to 5-10 membered cyclic, or R³ is 5-6 memberedheteroaryl optionally fused to 5-10 membered cyclic, either of which isoptionally substituted by one or more R⁸; each R⁸ is independently halo,nitro, —CN, OR³⁰, —NR³⁰R³¹, —C(O)R³⁰, —C(O)OR³⁰, —C(O)NR³⁰R³¹, —SR³⁰,—R³⁰, —NR³²C(O)NR³⁰R³¹, —OC(O)R³⁰, —NR³²C(O)R³⁰, —NR³²C(O)OR³⁰,—OC(O)NR³⁰R³¹, —C(O)—C(O)OR³⁰, —S(O₁₋₂)R³⁰, —S(O₁₋₂)NR³⁰R³¹,—NR³²S(O₁₋₂)R³⁰, —NR³²S(O₁₋₂)NR³⁰R³¹, —NR³¹S(O₁₋₂)OR³², or—OS(O₁₋₂)NR³⁰R³¹; or —PR³⁰R³¹, —P(OR³⁰)(OR³¹), —PR³⁰(OR³¹), —P(O)R³⁰R³¹,—P(O)(OR³⁰)(OR³¹), —P(O)R³⁰(OR³¹), —BR³⁰R³¹, —B(OR³⁰)(OR³¹),—NHS(O)(R³⁰)═NR³¹, or —R³⁰—S(O)(R³¹)═NR³²; wherein in the case of anon-aromatic moiety, an R⁸ can also be oxo; each R³⁰, R³¹, and R³² isindependently H or C₁₋₆aliphatic, each independently optionallysubstituted by one or more halo, oxo, nitro, —CN, —OR³³, —NR³³R³⁴,—C(O)R³³, —C(O)OR³³, —C(O)NR³³R³⁴, —SR³³, —R³⁴, —OC(O)R³³, —NR³⁴C(O)R³³,—NR³⁴C(O)OR³³, —N═CR³³R³⁴, —OC(O)NR³³R³⁴, —C(O)—C(O)OR³³, —S(O₁₋₂)R³³,—S(O₁₋₂)NR³³R³⁴, or —NR³³S(O₁₋₂)R³⁴; or by —PR³³R³⁴, —P(OR³³)(OR³⁴),—PR³³(OR³⁴), —P(O)R³³R³⁴, —P(O)(OR³³)(OR³⁴), —P(O)R³³(OR³⁴), —BR³³R³⁴,—B(OR³³)(OR³⁴), —NHS(O)(R³³)═NR³⁴, or —R³³—S(O)(R³⁴)═NR³⁵; wherein anyR³⁰/R³¹ pair attached to the same atom, together with said atom to whichthey are attached, can form a 3-6 membered cyclic that can include oneor more heteroatoms selected from O, NR³⁸, or S(O₀₋₂); each R³³, R³⁴,and R³⁵ is independently H or C₁₋₃aliphatic, each independentlyoptionally substituted by one or more halo, —CN, —OR³⁶, —NR³⁶R³⁷,—C(O)R³⁶, —C(O)OR³⁶, —C(O)NR³⁶, or —OC(O)R³⁶; wherein any R³³/R³⁴ pairattached to the same atom, together with said atom to which they areattached, can form a 3-6 membered cyclic that can include one or moreheteroatoms selected from O, NR³⁹, or S(O₀₋₂); and each R³⁶, R³⁷, R³⁸,and R³⁹ is independently H or C₁₋₃aliphatic.
 5. The compound or salt ofclaim 4, wherein: R⁸ is independently halo, nitro, —CN, —OR³⁰, —NR³⁰R³¹,—C(O)R³⁰, —C(O)OR³⁰, —C(O)NR³⁰R³¹, —SR³⁰, —R³⁰, —NR³²C(O)NR³⁰R³¹,—OC(O)R³⁰, —NR³²C(O)R³⁰, —NR³²C(O)OR³⁰, —OC(O)NR³⁰R³¹, —C(O)—C(O)OR³⁰,—S(O₁₋₂)R³⁰, —S(O₁₋₂)NR³⁰R³¹, —NR³²S(O₁₋₂)R³⁰, —NR³²S(O₁₋₂)NR³⁰R³¹, or—OS(O₁₋₂)NR³⁰R³¹; in the case of a non-aromatic moiety, an R⁸ can alsobe oxo; and each R³⁰, R³¹, and R³² is independently H or C₁₋₃aliphatic.6. The compound or salt of claim 5, having the formula:

wherein R⁵ is C₁₋₃aliphatic.
 7. The compound or salt of claim 6, whereinR⁵ is CH₃.
 8. The compound or salt of claim 1, wherein: A₁ is N; A₂ isCH((R)-methyl); R¹ is phenyl or pyridyl, either of which is optionallysubstituted by 1-2 independent halo, —CN, —CH₃, or —OC₁₋₃alkyl; R² isC₃₋₆aliphatic selected from branched and cyclic aliphatic optionallyinterrupted by 1-2 heteroatoms, and optionally substituted by 1-2independent halo, —CH₃, or —OCH₃; R³ is selected from:

wherein each A₃, A₄, A₅, and A₆ is independently CH or N; A₇ is CH₂, O,or S; and wherein either of the above is optionally substituted by 1-3independent halo, —CH₃, or —OCH₃ groups.
 9. The compound or salt ofclaim 1 selected from: 12-(1H-indazol-5-ylamino)-7-methyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one 22-[(3,5-difluoro-4-hydroxyphenyl)amino]-7-methyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one 37-methyl-8-(3-methylbutyl)-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]-5-phenyl-7,8-dihydropteridin-6(5H)-one 4 diethyl(4-{[7-methyl-8-(3-methylbutyl)-6-oxo-5-phenyl-5,6,7,8-tetrahydropteridin-2-yl]amino}benzyl)phosphonate 5N-methyl-2-(4-{[7-methyl-8-(3-methylbutyl)-6-oxo-5-phenyl-5,6,7,8-tetrahydropteridin-2-yl]aminolphenyl)acetamide 6N,N-dimethyl-2-(4-{[7-methyl-8-(3-methylbutyl)-6-oxo-5-phenyl-5,6,7,8-tetrahydropteridin-2-yl]amino}phenyl)acetamide 7N-methyl-1-(4-{[7-methyl-8-(3-methylbutyl)-6-oxo-5-phenyl-5,6,7,8-tetrahydropteridin-2-yl]aminolphenyl)methanesulfonamide 8N,N-dimethyl-1-(4-{[7-methyl-8-(3-methylbutyl)-6-oxo-5-phenyl-5,6,7,8-tetrahydropteridin-2-yl]aminolphenyl)methanesulfonamide 9 methyl4-{[7-methyl-8-(3-methylbutyl)-6-oxo-5-phenyl-5,6,7,8-tetrahydropteridin-2-yl]amino}benzoate 10 methyl3-{[7-methyl-8-(3-methylbutyl)-6-oxo-5-phenyl-5,6,7,8-tetrahydropteridin-2-yl]amino}benzoate 112-[(trans-4-hydroxycyclohexyl)amino]-7-methyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one 122-[(cis-4-hydroxycyclohexyl)amino]-7-methyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one 132-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-8-(propan-2-yl)-7,8-dihydropteridin-6(5H)-one 144-{[7-methyl-8-(3-methylbutyl)-6-oxo-5-phenyl-5,6,7,8-tetrahydropteridin-2-yl]amino}benzoic acid 153-{[7-methyl-8-(3-methylbutyl)-6-oxo-5-phenyl-5,6,7,8-tetrahydropteridin-2-yl]amino}benzoic acid 16(7R)-2-(1H-indazol-5-ylamino)-7-methyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one 17(7S)-2-(1H-indazol-5-ylamino)-7-methyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one 18(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one 194-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 20(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-(pyridin-4-yl)-7,8-dihydropteridin-6(5H)-one 21(7R)-5-(4-chlorophenyl)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 22(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-(4-methylphenyl)-7,8-dihydropteridin-6(5H)-one 23(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 24(7R)-8-cyclohexyl-5-(4-fluorophenyl)-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 25(7R)-8-cyclohexyl-5-(3-fluorophenyl)-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 26(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-5-(4-methoxyphenyl)-7-methyl-7,8-dihydropteridin-6(5H)-one 274-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-N,N-dimethylbenzamide 28(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-5-(3-methoxyphenyl)-7-methyl-7,8-dihydropteridin-6(5H)-one 293-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 30(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-(3-methylphenyl)-7,8-dihydropteridin-6(5H)-one 31(7R)-5-(3-chlorophenyl)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 323-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-N,N-dimethylbenzamide 33(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-[4-(trifluoromethoxy)phenyl]-7,8-dihydropteridin-6(5H)-one 34(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-[3-(trifluoromethoxy)phenyl]-7,8-dihydropteridin-6(5H)-one 35(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-[4-(trifluoromethyl)phenyl]-7,8-dihydropteridin-6(5H)-one 36(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-[3-(trifluoromethyl)phenyl]-7,8-dihydropteridin-6(5H)-one 374-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-N-methylbenzenesulfonamide 38(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-(3,4,5-trimethoxyphenyl)-7,8-dihydropteridin-6(5H)-one 39(7R)-5-(1,3-benzodioxol-5-yl)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 40(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-[4-(methylsulfonyl)phenyl]-7,8-dihydropteridin-6(5H)-one 41(7R)-8-cyclohexyl-5-[4-(dimethylamino)phenyl]-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 423-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-N-methylbenzenesulfonamide 43(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-[3-(methylsulfonyl)phenyl]-7,8-dihydropteridin-6(5H)-one 44(7R)-8-cyclohexyl-5-[3-(dimethylamino)phenyl]-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 45(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-(naphthalen-2-yl)-7,8-dihydropteridin-6(5H)-one 463-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-N-methylbenzamide 47N-{4-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]phenyl}methanesulfonamide 48(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-5-(6-methoxypyridin-3-yl)-7-methyl-7,8-dihydropteridin-6(5H)-one 49(7R)-8-cyclohexyl-5-(3,4-difluorophenyl)-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 50(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-(quinolin-3-yl)-7,8-dihydropteridin-6(5H)-one 513-[(7R)-8-cyclohexyl-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 52 methyl4-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzoate 535-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2-methylbenzonitrile 54(7R)-8-cyclohexyl-5-(4-fluoro-3-methoxyphenyl)-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 55(7R)-8-cyclohexyl-5-(3-fluoro-4-methoxyphenyl)-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 563-[(7R)-8-cyclohexyl-2-[(6-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 57(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-(thiophen-3-yl)-7,8-dihydropteridin-6(5H)-one 58(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one 593-[(7R)-8-cyclohexyl-7-methyl-2-[(7-methyl-1H-indazol-5-yl)amino]-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 608-cyclohexyl-7-methyl-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]-5-phenyl-7,8-dihydropteridin-6(5H)-one 618-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one 62(7S)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one 634-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzoic acid 648-cyclopentyl-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one 658-cyclopentyl-7-methyl-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]-5-phenyl-7,8-dihydropteridin-6(5H)-one 66(7R)-8-cyclopentyl-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one 67(7S)-8-cyclopentyl-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one 68(7R)-8-cyclopentyl-7-methyl-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]-5-phenyl-7,8-dihydropteridin-6(5H)-one 693-[(7R)-8-cyclopentyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 702-(1H-indazol-5-ylamino)-7,7-dimethyl-8-(3-methylbutyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one 713-[(7R)-8-(cyclobutylmethyl)-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 72(7R)-8-(cyclohexylmethyl)-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one 73(7R)-8-[2-(dimethylamino)ethyl]-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one 74(7R)-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-8-(tetrahydro-2H-pyran-4-ylmethyl)-7,8-dihydropteridin-6(5H)-one 75(7R)-8-(cyclopentylmethyl)-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one 76(7R)-8-benzyl-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one 77(7R)-8-(3-hydroxypropyl)-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one 78(7R)-2-(1H-indazol-5-ylamino)-7-methyl-5-phenyl-8-(piperidin-4-ylmethyl)-7,8-dihydropteridin-6(5H)-one 79(7R)-2-(1H-indazol-5-ylamino)-7-methyl-8-(2-methylpropyl)-5-phenyl-7,8-dihydropteridin-6(5H)-one 803-[(7R)-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-ylmethyl)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 813-[(7R)-8-(cyclopentylmethyl)-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 823-[(7R)-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-8-(tetrahydrofuran-3-ylmethyl)-7,8-dihydropteridin-5(6H)- yl]benzonitrile83 3-[(7R)-8-[(3,3-difluorocyclobutyl)methyl]-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)- yl]benzonitrile 85(7R)-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(3-methylbutyl)-7,8-dihydropteridin- 6(5H)-one 863-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(3-methylbutyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 87(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(3-methylbutyl)-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 88(7R)-5-(3,4-dimethoxyphenyl)-2-[(4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7-methyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one 893-[(7R)-2-[(3,5-difluoro-4-hydroxyphenyl)amino]-7-methyl-8-(3-methylbutyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 903-[(7R)-2-[(4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7-methyl-8-(3-methylbutyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 915-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(3-methylbutyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2- methoxybenzonitrile92 2-ethoxy-5-[(7R)-2-[(7-fluoro-1H-indazol-5--yl)amino]-7-methyl-8-(3-methylbutyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 935-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(3-methylbutyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2-(propan-2-yloxy)benzonitrile 947-methyl-2-[(2-oxo-2,3-dihydro-1H-indo1-5-yl)amino]-5-phenyl-8-(propan-2-yl)-7,8-dihydropteridin-6(5H)-one 95(7R)-8-cyclohexyl-5-(3,5-difluorophenyl)-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 965-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2-fluorobenzonitrile 973-[(7R)-2-[(7-chloro-1H-indazol-5-yl)amino]-8-cyclohexyl-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 98(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-[6-(methylsulfanyl)pyridin-3-yl]-7,8-dihydropteridin-6(5H)-one 99(7R)-8-cyclohexyl-5-(3-fluoro-5-methoxyphenyl)-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 1003-[(7R)-8-cyclohexyl-2-[(4-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1013-[(7R)-2-[(4-chloro-1H-indazol-5-yl)amino]-8-cyclohexyl-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1023-[(7R)-8-cyclohexyl-2-[(4-methoxy-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1033-[(7R)-8-cyclohexyl-7-methyl-2-[(3-methyl-1H-indazol-5-yl)amino]-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1045-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2-methoxybenzonitrile 1052-chloro-5-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1063-[(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1073-[(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-4-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1083-[(7R)-2-[(3-chloro-1H-indazol-5-yl)amino]-8-cyclohexyl-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1093-[(7R)-2-(1,2-benzothiazol-5-ylamino)-8-cyclohexyl-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 110(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-5-[3-(methoxymethyl)phenyl]-7-methyl-7,8-dihydropteridin-6(5H)-one 111(7R)-8-cyclohexyl-5-(3,4-dimethoxyphenyl)-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 1123-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-5-fluorobenzonitrile 113(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-(6-methylpyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 114(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-[3-(methylsulfinyl)phenyl]-7,8-dihydropteridin-6(5H)-one 1153-[(7R)-8-cyclohexyl-2-[(3-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1163-[(7R)-8-cyclohexyl-2-[(3-methoxy-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1173-[(7R)-8-cyclohexyl-7-methyl-2-[(4-methyl-1H-indazol-5-yl)amino]-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1183-[(7R)-2-[(6-chloro-1H-indazol-5-yl)amino]-8-cyclohexyl-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1193-[(7R)-8-cyclohexyl-2-[(6-methoxy-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 120(7R)-8-cyclohexyl-2-[(4-fluoro-1H-indazol-5-yl)amino]-5-(3-fluorophenyl)-7-methyl-7,8-dihydropteridin-6(5H)-one 121(7R)-8-cyclohexyl-5-(3-fluoro-4-methylphenyl)-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 122(7R)-8-cyclohexyl-2-[(4-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 1233-[(7R)-8-cyclohexyl-2-[(7-methoxy-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1244-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]thiophene-2-carboxylic acid 125(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-5-(3-methoxy-4-methylphenyl)-7-methyl-7,8-dihydropteridin-6(5H)-one 126(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-5-[4-(morpholin-4-yl)phenyl]-7,8-dihydropteridin-6(5H)-one 127(7R)-8-cyclohexyl-5-[3-(hydroxymethyl)phenyl]-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 1285-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]pyridine-3-carbonitrile 129(7R)-8-cyclohexyl-5[6-(dimethylamino)pyridin-3-yl]-2-(1H-indazol-5-ylamino)-7-methyl-7,8-dihydropteridin-6(5H)-one 1303-[(7R)-8-cyclohexyl-2-[(4,7-difluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1313-[(7R)-8-cyclohexyl-2-[(3,7-difluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 132(7R)-8-cyclohexyl-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-7,8-dihydropteridin-6(5H)-one 133(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(quinolin-7-yl)-7,8-dihydropteridin-6(5H)-one 134(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-[4-(morpholin-4-yl)phenyl]-7,8-dihydropteridin- 6(5H)-one 135(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 1365-[(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2- methoxybenzonitrile 137(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-(3-fluorophenyl)-7-methyl-7,8-dihydropteridin-6(5H)-one 138(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-(6-methoxypyridin-3-yl)-7-methyl-7,8-dihydropteridin-6(5H)-one 139(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-7,8-dihydropteridin-6(5H)-one. 1403-[(7R)-8-cyclopentyl-7-ethyl-2-(1H-indazol-5-ylamino)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 141(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-[6-(pyrrolidin-1-yl)pyridin-3-yl]-7,8-dihydropteridin-6(5H)-one 142(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-[6-(piperidin-1-yl)pyridin-3-yl]-7,8-dihydropteridin-6(5H)-one 143(7R)-8-cyclohexyl-5-[6-(dimethylamino)pyridin-3-yl]-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-7,8-dihydropteridin-6(5H)-one 1443-[(7R)-8-cyclohexyl-2-[(3,4-difluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1453-[(7R)-8-cyclohexyl-2-[(7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)- yl]benzonitrile 1463-[(7R)-8-cyclohexyl-7-methyl-6-oxo-2-[(3,4,7-trifluoro-1H-indazol-5-yl)amino]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 147(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-[6-(4-hydroxypiperidin-1-yl)pyridin-3-yl]-7-methyl-7,8-dihydropteridin-6(5H)-one. 1484-{[(7R)-8-cyclohexyl-5-(3,4-dimethoxyphenyl)-7-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}benzoic acid 1493-[(7R)-8-cyclohexyl-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-(6H)-yl]benzonitrile 150(7R)-8-cyclohexyl-5-(3,4-dimethoxyphenyl)-7-methyl-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin- 6(5H)-one151 (7R)-8-cyclohexyl-7-methyl-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-5-(pyridin-3-yl)-7,8-dihydropteridin- 6(5H)-one152 3-[(7R)-8-cyclohexyl-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 153(7R)-8-cyclohexyl-5-(3,4-dimethoxyphenyl)-7-methyl-2-(1H-pyrazolo[3,4-B]pyridin-5-ylamino)-7,8-dihydropteridin-6(5H)-one. 154(7R)-8-cyclohexyl-7-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 1554-{[(7R)-5-(3-cyanophenyl)-8-cyclohexyl-7-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}benzoic acid. 1563-[(7R)-8-cyclohexyl-7-methyl-6-oxo-2-(phenylamino)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1575-{[(7R)-5-(3-cyanophenyl)-8-cyclohexyl-7-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-1H-indazole-3-carbonitrile. 1583-[(7R)-8-cyclohexyl-2-[(3,5-difluoro-4-hydroxyphenyl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 159(7R)-8-cyclohexyl-2-[(3,5-difluoro-4-hydroxyphenyl)amino]-5-(3,4-dimethoxyphenyl)-7-methyl-7,8-dihydroptendin-6(5H)-one 160(7R)-8-cyclohexyl-2-[(3,5-difluoro-4-hydroxyphenyl)amino]-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin-(5H)-one. 1613-[(7R)-8-cyclohexyl-7-methyl-6-oxo-2-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-7,8-dihydroptendin-5(6H)-yl]benzonitrile 1645-[(7R)-8-cyclohexyl-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]-2-methoxybenzonitrile. 1655-[(7R)-8-cyclohexyl-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]-2-methoxybenzonitrile 1663-[(7R)-8-cyclohexyl-7-methyl-6-oxo-2-[(3-oxo-2,3-dihydro-1,2-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1673-[(7R)-8-cyclohexyl-7-methyl-6-oxo-2-(1H-pyrazolo[4,3-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1683-[(7R)-8-cyclohexyl-2-[(5-hydroxypyridin-2-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1693-[(7R)-8-cyclohexyl-2-[(4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1713-[(7R)-8-cyclohexyl-2-{[4-(hydroxymethyl)phenyl]aminol-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1723-[(7R)-8-cyclohexyl-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro[1,3]oxazolo[4,5-b]pyridin-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1735-[(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2-(4-methylpiperazin-1-yl)benzonitrile 1743-[(7R)-8-cyclohexyl-2-[(2,2-dioxido-1,3-dihydro-2,1-benzothiazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile. 175(7R)-8-cyclohexyl-7-methyl-5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-6(5H)-one 176(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7,8-dihydropteridin-6(5H)-one 177 methyl4-[(7R)-8-cyclohexyl-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]thiophene-2-carboxylate 1782-(1H-indazol-5-ylamino)-7-methyl-5,8-diphenyl-7,8-dihydropteridin-6(5H)-one 1797-methyl-2-[(2-oxo-2,3-dihydro-1H-indo1-5-yl)amino]-5,8-diphenyl-7,8-dihydropteridin-6(5H)-one 1803-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-8-(4-fluorophenyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-ypenzonitrile 1813-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-8-(3-methoxyphenyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1823-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-8-(4-methoxyphenyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1833-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-8-(3-fluorophenyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1843-[(7R)-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1853-[(7R)-2-[(4-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)- yl]benzonitrile186 3-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)- yl]benzonitrile187 (7R)-5-(3,4-dimethoxyphenyl)-2-[(3-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one 188(7R)-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one 189(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-(3-fluorophenyl)-7-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin- 6(5H)-one 1905-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]-2-methoxybenzonitrile 191(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(pyridin-3-yl)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one 192(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-(6-methoxypyridin-3-yl)-7-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one 193 (7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one 1943-[(7R)-2-[(3,5-difluoro-4-hydroxyphenyl)amino]-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1952-Ethoxy-5-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 1965-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]-2-(propan-2-yloxy)benzonitrile 1972-Methoxy-5-[(7R)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]benzonitrile. 1982-Ethoxy-5-[(7R)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]benzonitrile. 1995-[(7R)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]-2-(propan-2-yloxy)benzonitrile 2002-methoxy-5-[(7R)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2012-Ethoxy-5-[(7R)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]benzonitrile. 2025-[(7R)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]-2-(propan-2-yloxy)benzonitrile 2035-[(7R)-2-[(4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]-2-methoxybenzonitrile. 2042-Ethoxy-5-[(7R)-2-[(4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]benzonitrile. 2055-[(7R)-2-[(4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]-2-(propan-2-yloxy)benzonitrile. 2065-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-5(6H)-yl]-2-(4-methylpiperazin-1-yl)benzonitrile 2073-[(7R)-8-(4,4-dimethylcyclohexyl)-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin- 5(6H)-yl]benzonitrile 208(7R)-8-(4,4-dimethylcyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin- 6(5H)-one 2093-[(7R)-8-(4,4-dimethylcyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin- 5(6H)-yl]benzonitrile 210(7R)-5-(3,4-dimethoxyphenyl)-8-(4,4-dimethylcyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-7,8-dihydropteridin-6(5H)-one 211 (7R)-8-(4,4-dimethylcyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-(3-fluorophenyl)-7-methyl-7,8-dihydropteridin- 6(5H)-one 2125-[(7R)-8-(4,4-dimethylcyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2-(pyrrolidin-1-yl)benzonitrile 213(7R)-8-(4,4-dimethylcyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-[6-(morpholin-4-Apyridin-3-yl]-7,8-dihydropteridin-6(5H)-one 214(7R)-8-(4,4-dimethylcyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-[6-(pyrrolidin-1-yl)pyridin-3-yl]-7,8-dihydropteridin-6(5H)-one 215(7R)-8-(4,4-dimethylcyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-[6-(piperidin-1-yl)pyridin-3-yl]-7,8-dihydropteridin-6(5H)-one 2163-[(7R)-8-cyclopentyl-2-[(4-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2173-[(7R)-8-cyclopentyl-7-ethyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2183-[(7R)-8-cyclopentyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-(hydroxymethyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2193-[(7R)-8-cyclopentyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2203-[(7R)-8-cyclopentyl-7-(hydroxymethyl)-2-(1H-indazol-5-ylamino)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2213-[(7S)-8-cyclopentyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-(fluoromethyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2223-[(7S)-8-cyclopentyl-7-(fluoromethyl)-2-(1H-indazol-5-ylamino)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2233-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-8-(cis-4-methoxycyclohexyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2243-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-8-(trans-4-methoxycyclohexyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 225(7R)-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-8-(trans-4-methoxycyclohexyl)-7-methyl-7,8-dihydropteridin-6(5H)-one 226(7R)-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-8-(cis-4-methoxycyclohexyl)-7-methyl-7,8-dihydropteridin-6(5H)-one 227(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-8-(cis-4-methoxycyclohexyl)-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 2283-[(7R)-8-(cis-4-methoxycyclohexyl)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2293-[(7R)-8-(trans-4-methoxycyclohexyl)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2303-[(7R)-8-(trans-4-methoxycyclohexyl)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2313-[(7R)-8-(trans-4-methoxycyclohexyl)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2323-[(7R)-2-[(3,5-difluoro-4-hydroxyphenyl)amino]-8-(trans-4-methoxycyclohexyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile. 233(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-8-(trans-4-methoxycyclohexyl)-7-methyl-5-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-7,8-dihydropteridin-6(5H)-one 2342-methoxy-5-[(7R)-8-(trans-4-methoxycyclohexyl)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2352-methoxy-5-[(7R)-8-(trans-4-methoxycyclohexyl)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2363-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(cis-4-methylcyclohexyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2373-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(trans-4-methylcyclohexyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 238(7R)-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(cis-4-methylcyclohexyl)-7,8-dihydropteridin-6(5H)-one 239(7R)-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(trans-4-methylcyclohexyl)-7,8-dihydropteridin-6(5H)-one 240(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(cis-4-methylcyclohexyl)-5-(pyridin-3-yl)-7,8-dihydropteridin- 6(5H)-one 241(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(cis-4-methylcyclohexyl)-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 242(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(trans-4-methylcyclohexyl)-5-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-7,8-dihydropteridin-6(5H)-one 2433-[(7R)-2-[(3,5-difluoro-4-hydroxyphenyl)amino]-7-methyl-8-(trans-4-methylcyclohexyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile. 2442-methoxy-5-[(7R)-7-methyl-8-(trans-4-methylcyclohexyl)-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2452-Methoxy-5-[(7R)-7-methyl-8-(trans-4-methylcyclohexyl)-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2462-Ethoxy-5-[(7R)-7-methyl-8-(trans-4-methylcyclohexyl)-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2472-Ethoxy-5-[(7R)-7-methyl-8-(trans-4-methylcyclohexyl)-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)- yl]benzonitrile 2485-[(7R)-7-methyl-8-(trans-4-methylcyclohexyl)-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]-2-(propan-2-yloxy)benzonitrile. 2495-[(7R)-7-methyl-8-(trans-4-methylcyclohexyl)-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]-2-(propan-2-yloxy)benzonitrile 2503-[(7R)-2-[(2,2-dioxido-1,3-dihydro-2,1-benzothiazol-5-yl)amino]-7-methyl-8-(trans-4-methylcyclohexyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile. 2515-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(trans-4-methylcyclohexyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2-(4-methylpiperazin-1-yl)benzonitrile 2525-[(7R)-7-methyl-8-(trans-4-methylcyclohexyl)-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]-2-(4-methylpiperazin-1-yl)benzonitrile 2533-[(7R)-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-8-[trans-4-(trifluoromethyl)cyclohexyl]-7,8-dihydropteridin-5(6H)- yl]benzonitrile254 3-[(7R)-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-8-[cis-4-(trifluoromethyl)cyclohexyl]-7,8-dihydropteridin-5(6H)- yl]benzonitrile255 (7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(pyridin-3-yl)-8-[cis-4-(trifluoromethyl)cyclohexyl]-7,8-dihydropteridin-6(5H)-one 256(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(pyridin-3-yl)-8-[trans-4-(trifluoromethyl)cyclohexyl]-7,8-dihydropteridin-6(5H)-one 257 (7R)-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-[cis-4-(trifluoromethyl)cyclohexyl]-7,8-dihydropteridin-6(5H)-one 258(7R)-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-[trans-4-(trifluoromethyl)cyclohexyl]-7,8-dihydropteridin-6(5H)-one 2593-[(7R)-2-[(3,5-difluoro-4-hydroxyphenyl)amino]-7-methyl-6-oxo-8-[trans-4-(trifluoromethyl)cyclohexyl]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2603-[(7R)-8-(4,4-difluorocyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin- 5(6H)-yl]benzonitrile 2613-[(7R)-8-(4,4-difluorocyclohexyl)-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 262(7R)-8-(4,4-difluorocyclohexyl)-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-7,8-dihydropteridin-6(5H)-one 263(7R)-8-(4,4-difluorocyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-(3-fluorophenyl)-7-methyl-7,8-dihydropteridin- 6(5H)-one 264(7R)-8-(4,4-difluorocyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin- 6(5H)-one 2653-[(7R)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2663-[(7R)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2673-[(7R)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2683-[(7R)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-c]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2694-{[(7R)-5-(3-cyanophenyl)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}benzoic acid 2703-[(7R)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2714-{[(7R)-5-(3-cyanophenyl)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-2-fluorobenzoic acid 2724-{[(7R)-5-(3-cyanophenyl)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-2-fluorobenzamide 2734-{[(7R)-5-(3-cyanophenyl)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}benzenesulfonamide 2743-[(7R)-2-[(4-cyanophenyl)amino]-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2753-[(7R)-2-{[4-amino-3-(trifluoromethyl)phenyl]aminol-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2763-[(7R)-8-(4,4-difluorocyclohexyl)-2-[(3,5-difluoro-4-hydroxyphenyl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2773-[(7R)-8-(4,4-difluorocyclohexyl)-2-[(4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2785-[(7R)-8-(4,4-difluorocyclohexyl)-2-[(4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2-(propan-2-yloxy)benzonitrile 2795-[(7R)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]-2-methoxybenzonitrile 2805-[(7R)-8-(4,4-difluorocyclohexyl)-2-[(4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2-ethoxybenzonitrile 2815-[(7R)-8-(4,4-difluorocyclohexyl)-2-[(4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]-2-methoxybenzonitrile 2825-[(7R)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]-2-ethoxybenzonitrile 2835-[(7R)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]-2-methoxybenzonitrile 2845-[(7R)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]-2-ethoxybenzonitrile 2855-[(7R)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-2-[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]-7,8-dihydropteridin-5(6H)-yl]-2-(propan-2-yloxy)benzonitrile 2865-[(7R)-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]-2-(propan-2-yloxy)benzonitrile 2873-[(7R)-8-cyclohexyl-7-ethyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 288(7R)-8-cyclohexyl-7-ethyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 289(7R)-8-cyclohexyl-5-(3,4-dimethoxyphenyl)-7-ethyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7,8-dihydropteridin-6(5H)-one. 290(7R)-8-cyclohexyl-7-ethyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-(3-fluorophenyl)-7,8-dihydropteridin-6(5H)-one 291(7R)-8-cyclohexyl-7-ethyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-[3-(trifluoromethyl)phenyl]-7,8-dihydropteridin-6(5H)-one. 292(7R)-8-cyclohexyl-7-ethyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-[6-(morpholin-4-yl)pyridin-3-yl]-7,8-dihydropteridin-6(5H)-one 293(7R)-8-cyclohexyl-5-[6-(dimethylamino)pyridin-3-yl]-7-ethyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7,8-dihydropteridin-6(5H)-one 294(7R)-8-cyclohexyl-7-ethyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-5-(3-fluoro-4-methoxyphenyl)-7,8-dihydropteridin-6(5H)-one 2953-[(7R)-8-cyclohexyl-7-ethyl-2-[(3-fluoro-1H-indazol-5-yl)amino]-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2963-[(7R)-8-cyclopentyl-7-ethyl-2-(1H-indazol-5-ylamino)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 2973-[(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-8-(spiro[2.5]oct-6-yl)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 298(7R)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(pyridin-3-yl)-8-(spiro[2.5]oct-6-yl)-7,8-dihydropteridin-6(5H)-one. 299(7R)-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(spiro[2.5]oct-6-yl)-7,8-dihydropteridin- 6(5H)-one300 (7R)-8-[(2,2,3,3,4,4,5,5,6,6-2H10)cyclohexyl]-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-7,8-dihydropteridin-6(5H)-one 301(7R)-8-[(2,2,3,3,4,4,5,5,6,6-2H10)cyclohexyl]-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 3023-[(7R)-8-[(2,2,3,3,4,4,5,5,6,6-2H10)cyclohexyl]-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile 303(7R)-8-cyclohexyl-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(1-oxidopyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 304(7R)-8-(4,4-dimethylcyclohexyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-5-(1-oxidopyridin-3-yl)-7,8-dihydropteridin-6(5H)-one 3052-(1H-indazol-5-ylamino)-8-(3-methylbutyl)-5-phenyl-5,8-dihydropteridine-6,7-dione 3068-(3-methylbutyl)-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]-5-phenyl-5,8-dihydropteridine-6,7-dione 3078-cyclopentyl-2-(1H-indazol-5-ylamino)-5-phenyl-5,8-dihydropteridine-6,7-dione 308(7R)-5-(3,4-dimethoxyphenyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-8-(4-oxocyclohexyl)-7,8- dihydropteridin-6(5H)-one309 3-[(7R)-8-(cis-4-hydroxycyclohexyl)-2-(1H-indazol-5-ylamino)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)- yl]benzonitrile 3113-[(7R)-8-(3,3-dimethylcyclobutyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)- yl]benzonitrile 3123-[(7R)-8-(3,3-dimethylcyclobutyl)-7-methyl-6-oxo-2-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)-7,8-dihydropteridin-5(6H)-yl]benzonitrile 3133-[(7R)-8-(3,3-difluorocyclobutyl)-2-[(7-fluoro-1H-indazol-5-yl)amino]-7-methyl-6-oxo-7,8-dihydropteridin- 5(6H)-yl]benzonitrile.


10. A pharmaceutical composition comprising the compound or salt ofclaim 1, formulated with one or more pharmaceutical carriers.